Carboxyalkenamidocephalosporins

ABSTRACT

An antibacterial 7beta-(carboxyalkenoyl)amino-3-cephem-4-carboxylic acid represented by the following formula: ##STR1## (wherein R is aryl or a heterocyclic group; 
     R 1  is hydrogen or halogen; 
     R 2  is a single bond, alkylene, or thiaalkylene; 
     R 3  is a hydrogen atom or carboxy modifying group; 
     R 4  is hydrogen or methoxy; 
     R 5  is hydrogen or a 3-substituent of cephalosporins; 
     R 6  is a hydrogen atom or carboxy modifying group; and 
     X is oxygen, sulfur, or sulfinyl) 
     a pharmaceutical composition containing the same, and a method for treating a bacterial infection with the same.

This application is a division of application Ser. No. 831,435, filedFeb. 20, 1986, (now U.S. Pat. No. 4,748,170) which application is adivision of application Ser. No. 711,017, filed Mar. 12, 1985 (now U.S.Pat. No. 4,634,697), which application is in turn, acontinuation-in-part of application Ser. No. 656,731, filed Oct. 1, 1984(now abandoned).

This invention relates to antibacterial7beta-(carboxyalkenoylamino)-3-cephem-4-carboxylic acids represented bythe following formula: ##STR2## (wherein R is aryl or a heterocyclicgroup;

R¹ is hydrogen or halogen;

R² is a single bond, alkylene, or thiaalkylene;

R³ is a hydrogen atom or carboxy modifying group;

R⁴ is hydrogen or methoxy;

R⁵ is hydrogen or a 3-substituent of cephalosporins;

R⁶ is hydrogen atom or carboxy modifying group; and

X is oxygen, sulfur, or sulfinyl)

The following explains the variable groups of the formula (I):

R as aryl is optionally substituted phenyl. R as a heterocyclic group isan optionally substituted 5 or 6 membered monocyclic ring groupcontaining 1 to 4 hetero atoms selected from oxygen, nitrogen, andsulfur. Representative rings are pyrryl, furyl, thienyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, thiatriazolyl, pyridyl,pyrimidyl, pyrazinyl, triazinyl, and the like. Here, the saidsubstituents include, among other conventional ones, alkyl, substitutedalkyl, carboxy, protected carboxy, amino, protected amino, hydroxy,protected hydroxy, halogen, sulfamoyl, and the like. Among theprotecting groups in the protected amino, preferably are 7 to 20 Coptionally substituted aralkyl (e.g., benzyl, benzhydryl, trityl,methoxybenzyl, dimethoxybenzyl, nitrobenzyl, methylbenzyl,dimethylbenzyl), 1 to 8 C optionally substituted alkyl (e.g.,trichloromethyl, trichloroethyl, trifluoromethyl, tetrahydropyranyl),substituted phenylthio, 1 to 8 C substituted alkylidene, 7 to 14 Csubstituted aralkylidene, 5 to 8 C substituted cycloalkylidene, acyl[e.g., 1 to 8 C optionally substituted alkanoyl (e.g., formyl, acetyl,chloroacetyl, trifluoroacetyl), 2 to 12 C optionally substituted loweralkoxycarbonyl (in which the alkyl part is methyl, ethyl, propyl,cyclopropylethyl, isopropyl, butyl, pentyl, hexyl, trichloroethyl,pyridylmethyl, cyclopentyl, cyclohexyl, quinolylmethyl, or the like), 8to 15 C optionally substituted aralkoxycarbonyl (in which the aralkylpart is benzyl, diphenylmethyl, nitrobenzyl, or the like), succinyl,phthaloyl], trialkylsilyl, alkoxydialkylsilyl, trialkylstannyl, and thelike.

Preferably R is one selected from phenyl, furyl, thienyl, oxazolyl,isoxazolyl, optionally protected aminoisoxazolyl, thiazolyl, optionallyprotected aminothiazolyl, thiadiazolyl, and aminothiadiazolyl. Anoptionally protected aminothiazolyl is more preferable.

R¹ as halogen is fluorine or chlorine, especially chlorine. PreferablyR¹ is hydrogen.

The alkylene part in R² is lower alkylene, preferably 1 to 3 C alkylene,especially methylene.

R⁵ as a substituent of cephalosporins can be, among others, hydroxy,alkanoyloxy, halogen, alkoxy, alkylthio, alkenylthio, alkyl (e.g.,methyl), alkenyl (e.g., vinyl, cyanovinyl, trifluoropropenyl),substituted methyl, or the like which are well known 3-substituents ofcephalosporins. Here, the substituent in the said substituted methyl canbe pyridinio, substituted pyridinio, halogen, hydroxy, alkoxy, acyloxy(e.g., acetoxy, carbamoyloxy), alkylthio, haloalkylthio, cyanoalkylthio,heterocyclic thio (e.g., triazolylthio, methyltetrazolylthio,thiadiazolylthio optionally substituted by amino, aminomethyl, alkoxy,or methyl), triazolyl, tetrazolyl, or the like. The alkyl part ispreferably methyl. Preferably R⁵ is hydrogen, vinyl, carbamoyloxymethyl,tetrazolylthiomethyl, or thiadiazolylthiomethyl.

R³ or R⁶ as a carboxy-modifying group is preferably an ester forminggroup or salt forming atom or group each useful as a carboxy-protectinggroup or one for a medical derivative.

Preferably X is sulfur.

The said carboxy-protecting group is known in penicillin andcephalosporin fields as it can be introduced and removed without adverseeffect on other parts of the molecule. Representative are an inorganicsalt (e.g., lithium, sodium, potassium, magnesium, calcium, aluminum, orammonium salt), organic base salt, for example, alkylamine salt (e.g.,ethylamine, diethylamine, triethylamine, piperidine, morpholine,N-methylmorpholine salt), aromatic amine salt (e.g., aniline,dimethylaniline salt), aromatic base salt (e.g., pyridine, picoline,lutidine, nicotinamide, quinoline salt), optionally substituted 1 to 8 Calkyl ester (e.g., methyl, methoxymethyl, ethoxymethyl, ethyl,methoxyethyl, trichloroethyl, iodoethyl, propyl, isopropyl, ethoxyethyl,methylthioethyl, methanesulfonylethyl, methanesulfonylmethyl, butyl,isobutyl, t-butyl, hexyl ester), 7 to 15 C aralkyl ester (e.g., benzyl,methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl,aminobenzyl, phenethyl, diphenylmethyl, trityl, phthalidyl, phenacyl,di-t-butyl-hydroxybenzyl ester), 6 to 12 C aryl ester (e.g., phenyl,tolyl, diisopropylphenyl, xylyl, trichlorophenyl, indanyl ester), 3 to12 C silyl ester (e.g., trimethylsilyl, t-butyldimethylsilyl,dimethylmethoxysilyl ester), 3 to 12 C stannyl ester (e.g.,trimethylstannyl ester), 1 to 12 C N-hydroxyamino ester (ester withe.g., acetone oxim, acetophenone oxim, acetalaoxim,N-hydroxysuccinimide, N-hydroxyphthalimide), 2 to 7 C alkenyl ester(e.g., vinyl, propenyl, allyl ester), and the like. Anhydrides withcarbonic or carboxylic acid, reactive amides, and the like areequivalent caboxy-protecting group. Said protecting part may further besubstituted.

Preferably R³ and R⁶ as carboxy protecting groups are hydrogen, sodium,potassium, methyl, t-butyl, phenyl, indanyl, benzyl, cyanobenzyl,halobenzyl, methylbenzyl, nitrobenzyl, phenylbenzyl, or the like.

The protecting group is absent in objective products. So, its structurehas in itself no specific means, as far as the group serves well for theprotection and thus it can be replaced by a wide variety of equivalentgroups.

Especially useful carboxy derivatives are medically available onesincluding light metal salts and pharmaceutically acceptable esters. Thepreferred light metals are those forming physiologically acceptable ionsand belonging to the 1st to 3rd group, 2nd to 4th periods of thePeriodical Table. Lithium, sodium, potassium, magnesium, calcium,aluminum, and the like are preferable. The pharmacological esters showantibacterial potency on administering orally or parenterally andincluding well known 3 to 12 C 1-substituted alkyl esters, for example,alkanoyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl,propionyloxyethyl, pivaloyloxymethyl, pivaloyloxyethyl, tetrahydrofuryl,tetrahydropyranyl ester), 3 to 8 C alkoxyformyloxyalkyl esters (e.g.,ethoxycarbonyloxyethyl ester), 7 to 15 C substituted aralkyl esters(e.g., phenacyl, phthalidyl ester), 6 to 12 C substituted aryl esters(e.g., phenyl, xylyl, indanyl ester), and 2-alkenyl esters (e.g., allyl,2-oxo-1,3-dioxclenylmethyl ester).

Both of the geometric isomers at the double bond in the 7-side chain areantibacterials. Among them, those having the R and R¹ in the cisposition are more potent antibacterials. The other geometric isomers(trans) are useful also as an intermediate for preparing thecorresponding cis isomer.

Some of the representative Compounds (I) of this invention are listedbelow. These should not be taken as an exhaustive listing of thecompounds of this invention.

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-methyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-vinyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]3-trifluoropropenyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-acetoxymethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-methoxymethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-methylthiomethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cyanomethylthiomethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-pyridiniomethyl-3-cephem-4-caroboxylate,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-triazolylthiomethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-thiadiazolylthiomethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-methyltetrazolyltniomethyl-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-methoxy-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-chloro-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-fluoroethylthio-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-trifluoroethylthio-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-5-carboxy-2-pentenoylamino]-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-6-carboxy-2-hexenoylamino]-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-2-pentenoylamino]-3-cephem-4-carboxylicacid,

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-4-methyl-2-pentenoylamino]-3-cephem-4-carboxylicacid, and

7beta-[2-(2-aminothiazol-4-yl)-4-carboxy-3-chloro-2-butencylamino]-3-cephem-4-carboxylicacid.

Some compounds closely related to Compounds (I) are disclosed inJapanese patent publication Kokoku 10,996/1967, Kokai 57-93982, andBelgian Pat. Nos. 816,408 and 888,389. These are not superior toCompounds (I) in their antibacterial activity, enteral or parenteralabsorbability, excretion, or the like characteristics.

Compounds (I) are antibacterials against aerobic Grampositive bacteria(e.g., Bacillus cereus, Bacillus subtilis, Corynebacterium diphtheriae,Staphylococcus aureus, Staphylococcus epidermidis, Streptococcuspneumoniae, Streptococcus pyogenes, Streptococcus viridans, enterococci)and Gramnegative bacteria (e.g., Citrobacter diversus, Citrobacterfreundii, Enterobacter aerogens, Enterobacter cloacae, Escherichia coli,Haemophilus influenzae, Klebsiella pneumoniae, Neisseria gonorrhoeae,Neisseria meningitidis, Proteus mirabilis, Proteus morganii, Proteusvulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonasaeruginos, Salmonella paratyphi, Salmonella typhi, Serratia marcescens,Shigella sonnei, Yersinia enterocolitica), including anaerobic bacteria(e.g., Bacteroides fragilis, Clostridium difficile, Clostridiumperfringens, Eubacterium lentum, Fusobacterium nucleatum,Propionibacterium spp, peptostreptococci, Veillonella spp.).

Especially, high anti-Gram-negative potency, high absorption, excretion,distribution, and the like are remarkable. As a medicine for preventingor treating a bacterial infection, Compound (I) is administered orally,parenterally, or topically at a daily dose of 10 micrograms to 6 grams,if required formulating with conventional additives or coactingsubstances, e.g., other antibacterials.

They are useful as bacteriocidal, bacteriostatic, disinfecting, orantiperishable agents and useful for treating of preventing human,veterinary, or poultry infections caused by sensitive Gram-positivebacteria or Gram-negative bacteria, including anaerobic bacteria.Further, they are useful as bacterial growth inhibitors on human,animal, plant, or perishable subjects, human or animal growth promotingadditives in foodstuff, or as an agents for testing sensitivity ofbacteria to the antibacterial (I).

Protected compounds (I) are also useful as starting materials forsynthesizing other antibacterials (I).

This invention also provides a method for treating or preventing humanor veterinary bacterial infections (e.g., abscess, bronchitis,dermatitis, ear infections, empyema, enteritis, gastroenteritis,nasopharyngitis, osteomyelitis, pneumonitis, pneumonia, pustulosis,pyelonephritis, respiratory tract infections, rhinitis, septicemia,tonsillitis, ulceration, urinary tract infections, wound and soft tissueinfections) caused by sensitive bacteria by administering an effectiveamount of Compound (I) at a typical daily dose of 10 micrograms to 1gram externally, 0.2 to 5 grams intravenously, or 0.1 to 2 grams orallyat an interval of 3 to 12 hours depending on the infecting bacteria andcondition of the patient, if required formulating with a conventionaladditive.

Compound (I) as carboxylic acid or its light metal salt can be injectedor infused intravenously, intramuscularly or subctaneously (as e.g.,injection, pellet), or given orally (as oral preparations, e.g.,capsule, dry syrup, emulsion, granules, powder, solution, suspension,tablet, troche), if required in admixture with an excipient (e.g.,emulsifying agent). A pharmacological ester can be given intravenously,intramuscularly, subctaneously, orally, externally, or topically (ase.g., ear, nasal, or ocular drug, ointment, inhalant, injection, pappreparation, spray, suppository).

When R is 2-amino-4-thiazolyl, R² is methylene, R¹, R³, R⁴, and R⁶ arehydrogens, and R⁵ is hydrogen, methyl, methoxymethyl,carbamoyloxymethyl, methylthiomethyl, cyanomethylthiomethyl, vinyl,fluoropropenyl, methoxy, chlorine, fluoroethylthio, ortrifluoroethylthio, Compound (I) is absorbed orally as well assubcutaneously. Its pharmaceutically acceptable esters are also absorbedthrough the digestive organs.

Further, this invention provides an antibacterial pharmaceuticalcomposition containing Compound (I) in various enteral or parenteraldosage forms solely or in admixture with carriers or coactingsubstances. The compositions may contain 0.01 to 99% of Compound (I)dissolved, dispersed, or suspended in solid or liquid pharmaceuticalcarriers.

The compositions may be solid preparations (e.g., capsule, dry syrup,granule, pellet, pill, powder, suppository, troche, tablet) or liquidpreparations (e.g., dispersion, elixir, emulsion, inhalant, injection,ointment, suspension, syrup, solution from ampoule or vial containingcrystals, lyophilized material, or powder). They can be flavored orcolored, and capsules, granules, and tablets may be coated. They can bein a unit dosage form.

The carriers are harmless to both the Compound (I) and patients.Representative examples of such carriers are, among others, for solids,binders (e.g., acacia, carboxymethylcellulose, gelatin, glucose,polyvinylpyrrolidone, sodium alginate, sorbitol, starch, syrup,tragacanth), bulking agents (e.g., bentonite, calcium carbonate, calciumphosphate, glycine, kaolin, lactose, polycarboxymethylene, salt,sorbitol, starch, sugar, talc), diluents (e.g., calcium carbonate,kaolin, lactose, starch, sucrose), disintegrators (e.g., agar,carbonates, sodium laurylsulfate, starch), lubricants (e.g., boric acid,cacao oil, magnesium stearate, paraffin, polyethylene glycol, silica,sodium benzoate, stearic acid, talc), and wetting agents (e.g.,hydroxypropyl cellulose); for solutions, solvents (e.g., alcohol,buffer, methyl cleate, peanut oil, sesame oil, water), emulsifyingagents (e.g., acacia, lethicin, sorbitan monooleate), suspending agents(e.g., aluminum stearate gel, carboxymethyl cellulose, gelatin, glucose,hydrogenated fats, hydroxyethylcellulose, methyl cellulose, sorbitol,sugar syrup), buffers, dispersing agents, and solubilizing agents; andfor both, preservatives (e.g., methyl or ethyl p-hydroxybenzoate, sorbicacid), absorption promoters (e.g., glycerin mono- or di-octanoate),antioxidants, aromatic substaces, analgesics, edible coloring agents,stabilizing agents, and the like.

All of above pharmaceutical preparations can be prepared in conventionalmanner.

This invention also provides Carboxyalkenoic acid (10) useful as anintermediate for preparing the said Compound (I) ##STR3## (wherein R,and R¹ to R⁶ are as defined for Compound (I).

In the formula above, examples of the preferred R are phenyl, thienyl,aminoisoxazolyl, thiadiazolyl, aminothiadiazolyl, and aminothiazolyl,said amino can be protected with benzyloxycarbonyl,methylbenzyloxycarbonyl, t-butoxycarbonyl, methoxyethoxymethyl, formyl,chloroacetyl, benzylidene, dimethylaminomethylidene, or the like;preferably R¹ is hydrogen; preferably R² is 1 to 3 C optionally branchedalkylene, especially methylene; and examples of preferred R³ and R⁶ arethe same or different groups selected from hydrogen, methyl, ethyl,t-butyl, trichloroethyl, benzyl, methylbenzyl, diphenylmethyl, trityl,and the like.

Compounds of this invention can be synthesized, for example, by thefollowing methods:

(1) Salt formation

Compound (I) having carboxy on the cephem nucleus at position 4 or inthe 7-substituent can form a light metal salt (I) by reacting with abase or by an exchange reaction with the corresponding light metal saltof other carboxylic acid. The procedure can be that conventional in theart, e.g., by neutralizing the free acid (with a base, e.g., light metalhydroxide, carbonate, or hydrogen carbonate) and evaporating thesolvent, or by treating with light metal lower carboxylate in a polarorganic solvent (e.g., alcohol, ketone, ester) and then adding asparingly dissolving less polar solvent to separate the salt. Thesolvent may be removed by filtering.

(2) Deprotection of carboxy-protecting groups etc,

A protected-carboxy in Compound (I) can conventionally be deprotected,for example, as follows:

(a) A highly reactive ester of anhydride as a carboxy-protecting groupcan be deprotected by contacting in an aqueous solvent with an acid,base, buffer solution, or ion exchange resin. When its reactivity isinsufficient, one can increase it in a conventional manner to deprotectmore easily (e.g., by activating of a trichloroethyl ester with metaland acid; p-nitrobenzyl ester with hydrogen and catalyst (e.g.,palladium, nickel), dithionate, or metal and acid; and phenacyl esterwith irradiation).

(b) An aralkyl ester can be deprotected by a conventional catalyticreduction with hydrogen in the presence of a catalyst (e.g., platinum,palladium, nickel).

(c) An aralkyl, cyclopropylmethyl, sulfonylethyl, or the like ester canbe deprotected by solvolyzing [with a mineral acid, Lewis acid (e.g.,aluminium chloride, tin chloride, titanium tetrachloride), sulfonic acid(e.g., methanesulfonic acid, trifluoromethanesulfonic acid), strongcarboxylic acid (trifluoroacetic acid), or the like], if required in thepresence of a cation scavenger.

An amino-protecting group in Compound (I) can conventionally bedeprotected, for example, as follows: substituted alkyl (e.g.,tetrahydropyranyl), aralkyl group (e.g., trityl), alkylidene,aralkylidene, alkanoyl (e.g. formyl), trialkylsilyl, trialkylstannyl, orthe like can be deprotected with an aqueous or nonaqueous acid; analkoxyformyl (e.g., t-butoxycarbonyl), aralkoxyformyl (e.g.,benzyloxycarbonyl, methylbenzyloxycarbonyl), aralkyl (e.g., trityl), orthe like can be deprotected with a Lewis acid in the presence of an acidscavenger; haloalkoxylcarbonyl (e.g., trichloroethyl,iodoethoxycarbonyl), aralkoxycarbonyl (e.g., benzyloxycarbonyl), or thelike can be deprotected by reduction; and phenylthio or acyl (e.g.,alkanoyl, succinyl, phthaloyl) can be deprotected with a base.

Deprotection of other protecting groups for hydroxy or the likefunctional groups in Compound (I) can be carried out according tomethods well known in the field of penicillin and cephalosporinchemistry as described in various scientific and patent publications.

(3) Amidation ##STR4##

A conventional reaction of Amine (II) or its reactive derivative withCarboxylic acid (III) or its reactive derivative gives Compound (I) orits derivatives.

The reactive derivative of Amine (II) is that having 7-amino activatedby silyl (e.g., trimethylsilyl, methoxydimethylsilyl,t-butyldimethylsilyl), stannyl (e.g., trimethylstannyl), alkylene (as apart of enamino of the amino with e.g., aldehyde, acetone,acetylacetone, acetoacetate, acetoacetonitrile, acetoacetanilide,cyclopentanedione, acetylbutyrolactone), alkylidene (e.g.,1-haloalkylidene, 1-haloaralkylidene, 1-alkoxyalkylidene,1-alkoxyaralkylidene, 1-alkoxy-1-phenoxyalkylidene, alkylidene,aralkylidene), acid (e.g., mineral acid, carboxylic acid, sulfonic acidas a salt of the amino), easily removable acyl (e.g., alkanoyl), or thelike, or that protected at other functions of the molecule.

Free acid (III) is reacted in the presence of condensing reagent[carbodiimide (e.g., N,N'-diethylcarbodiimide,N,N'-dicyclohexylcarbodiimide), carbonyl compound (e.g., carbonyldiimidazole), isoxazolinium salt, acylamino compound (e.g.,2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), etc.].

The reactive derivative of Carboxylic acid (III) can be an acidanhydride, e.g., symmetric anhydride or mixed anhydride [with mineralacid (e.g., phosphoric acid, sulfuric acid, hydrohalogenic acid,carbonic half ester), organic acid (e.g., alkanoic acid, aralkanoicacid, sulfonic acid), intramolecular anhydride (e.g., ketene,isocyanate), etc.]. acid halide, reactive ester [enol ester (e.g., vinylester, isopropenyl ester), aryl ester (e.g., phenyl ester, halophenylester, nitrophenyl ester), heterocyclic ester (e.g., pyridyl ester,benzotriazolylester), an ester with N-hydroxy compound,diacylhydroxylamine ester (e.g. N-hydroxysuccinimide ester,N-hydroxyphthalimide ester), thioester (e.g., aralkyl thiol ester,heterocyclic thiol ester) or the like], or reactive amide [aromaticamide (amide with e.g., imidazole, triazole,2-ethoxy-1,2-dihydroquinoline), diacylanilide]. The acid scavenger to beused with the said derivative is, for example, inorganic base (e.g.,oxide, hydroxide, carbonate, hydrogen carbonate, of alkali metal oralkaline earth metal, etc.), organic base (e.g., tertiary amine,aromatic base), oxirane, (e.g., alkylene oxide, aralkylene oxide),pyridinium salt (e.g., tripyridiniumtriazine trichloride), adsorbent(e.g., Celite), or the like.

(4) Introduction of 3function

Compound (I) having 3-nucleophile substituted-methyl can be prepared byreacting an analog of Compound (I) having a leaving group-substitutedmethyl at the 3-position on the cephem ring with a heterocyclic thiol,aromatic base, or its reactive derivatives. Here, the leaving group canbe, among others, halogen, sulfonyloxy, alkanoyloxy, dihaloalkanoyloxy,trihaloacetoxy, or the like. The said reactive derivative of thiol canbe, among others, alkali metal salt, ammonium salt, carboxylate ester,or the like. The reaction can be carried out well in a dry or wetsolvent at 0° C. to 60° C. This reaction can be promoted with adehydrating reagent, phosphoryl chloride compound, rhodanate, or thelike.

Compound (I) having 3-acyloxymethyl (e.g., alkanoyloxymethyl,carbamoyloxymethyl) can be made from the corresponding 4-protectedcarboxy-3-hydroxymethyl-3-cephem derivative by the action of anacylating reagent for introducing the corresponding acyl group.

Compound (I) having no carbon linked to the 3 position can be made fromthe corresponding 3-hydroxy-3-cephem or its oxo form, for example, byactivating the 3-hydroxy (e.g., acylating or halogenating), and thensubstituting it with a nucleophilic reagent to give a 3-nucleophilesubstituted compound; a basic or thermal elimination reaction of thecorresponding 3-(hydroxy, acyloxy, or halo) cepham compounds or areduction of 3-(acyloxy or halo)-3-cephem compounds to give a3-hydrogen-3-cephem compound; or the like conventional 3-modification.

(5) Isomerization at the 7-side chain double bond ##STR5##

The said geometric isomers are interconvertible by isomerization. Thisreaction is preferably carried out in a protic solvent by the action ofacid, base, or light. The acid can be a mineral acid (e.g., hydrochloricacid, sulfuric acid, phosphoric acid), carboxylic acid (e.g., formicacid, trifluoroacetic acid), sulfonic acid (e.g., methanesulfonic acid,benzenesulfonic acid), or the like. The base can be inorganic base(e.g., sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate), organic base (e.g., triethylamine, potassium t-butoxide), orthe like.

Compound (I) wherein R² is 1 to 3 C alkylene easily isomerizes undervarious conditions.

In a typical condition, Compound (I) as free carboxylic acid isdissolved in water at pH 8, acidified to pH 0 to 1, kept at 0° C. to100° C. for 1 to 10 hours to obtain an epimic mixture. Thermally stableisomer is in trans form. Usual separation (e.g., crystallization,precipitation, high precision liquid chromatography, adsorption andelution) gives the geometric isomers in a pure form.

(6) Other synthetic methods

(a) Sulfoxide formation:--Cephem compound (I) is conventionally oxidizedwith an oxidizing reagent (e.g., hydrogen peroxide, percarboxylic acid,iodobenzene dichloride) in an inert solvent at 0° to 60° C. for 0.2 to 5hours to give the corresponding Cephem-1-oxide (I).

(b) Sulfoxide reduction:--Cephem-1-oxide compound (I) is reducedconventionally with a trivalent phosphorus compound, lower valent metalcompound, hydrogen iodide, or the like in an inert solvent at 0° to 80°C. for 0.1 to 10 hours giving the corresponding Cephem compound (I).

(c) Double bond migration:--The 2-double bond of the corresponding2-cephem compound is conventionally migrated with base at 0° to 80° C.for 1 to 10 hours to give 3-Cephem compound (I).

(d) Ring closure:--Compound (I) may be synthesized by a conventionalring closure reaction forming a heterocyclic R group in a manneranalogous to those described above under the section of (7) Synthesis ofthe side chain acids.

(7) Synthesis of the side chain fragment acids

The 7side chain acids are novel compounds prepared by Wittig typereaction of Formylacetate (IV) or its enol or acetal withAlkylidenetriarylphosphorane (V) by heating, e.g., at 30° C. to 120° C.for 1 to 10 hours, to give Nonconjugated ester (VI) the double bond ofwhich migrates to give Conjugate ester (VII): ##STR6## (wherein and R²⁰is alkylene or a single bond) or of Oxalate (VIII) withAlkylidenetriarylphosphorane (IX), e.g., at 30° C. to 120° C. for 1 to10 hours to give Conjugate ester (VII).

alternatively, it is produced by a ring closure of Haloacetylcarboxylicacid (X) with optionally N-protected thiourea (XI) in alcohol at 30° C.to 90° C. for 1 to 5 hours giving Aminothiazole ester (XII): ##STR7##(wherein R²¹ is hydrogen or amino protecting group).

When R³ and/or R⁶ of Conjugated acid (VII) or (XII) is a carboxyprotecting group, it may be deprotected conventionally by treating withacid, base, Lewis acid and cation scavenger, hydrogen and catalyst, orthe like to give the corresponding free acid, preferably in an inertsolvent at -60° C. to 100° C. for 1/6 to 10 hours.

Representative synthesis of the side chain carboxylic acids are givenunder the section of Preparations.

(8) Reaction Conditions

The said reaction (1) to (7) can usually be carried out at -60° C. to120° C., preferably at -20° C. to 80° C. for 10 minutes to 10 hoursdepending on the type of reaction. These are done in a solvent. Otherconventional conditions (e.g., stirring, shaking, inert gas sealing,drying) may be used.

Examples of typical reaction solvents are hydrocarbons (e.g., pentane,hexane, octane, benzene, toluene, xylene), halohydrocarbons (e.g.,dichloromethane, chloroform, carbon tetrachloride, dichloroethane,trichloroethane, chlorobenzene), ethers (e.g., diethyl ether, methylisobutyl ether, dioxane, tetrahydrofuran), ketones (e.g., acetone,methyl ethyl ketone, cyclohexanone), esters (e.g., ethyl acetate,isobutyl acetate, methyl benzoate), nitrohydrocarbons (e.g.,nitromethane, nitrobenzene), nitriles (e.g., acetonitrile,benzonitrile), amides (e.g., formamide, acetamide, dimethylformamide,dimethylacetamide, hexamethylphosphorotriamide), sulfoxides (e.g.,dimethyl sulfoxide), carboxylic acids (e.g., formic acid, acetic acid,propionic acid), organic bases (e.g., diethylamine, triethylamine,pyridine, picoline, collidine, quinoline), alcohols (e.g., methanol,ethanol, propanol, hexanol, octanol, benzyl alcohol), water, and otherindustrial solvents and mixtures thereof.

(9) Work up

The products can be obtained from a reaction mixture by removingcontaminants (e.g., solvents, unreacted starting materials, by-products)by a conventional method (e.g., extracting, evaporating, washing,concentrating, precipitating, filtrating, drying), and isolating theproduct by a usual work up (e.g., adsorbing, eluting, distilling,precipitating, separating, chromatographing), or a combination of saidprocedures.

(10) Oral availability

Some compounds (I) having methylene as R² are absorbed well through thedigestive organs and are available as oral cephalosporins. Especiallyefficient are those having 2-aminothiazol-4-yl as R, hydrogen as R³ andR⁶, and hydrogen, vinyl, cyanovinyl, trifluoropropenyl, acetoxymethyl,carbamoyloxymethyl, or thiadiazolylthiomethyl as R⁵ and salts of these.It is to be noted that compounds (I) having a single bond, dimethylene,or trimethylene as R² or that having no carboxylic 7beta-side chain arepractically unabsorbed enterally. A compound having amino in R can forma salt by mixing with an acid, e.g., mineral acid (e.g. HCl), carboxylicacid (TFA).

EXAMPLES

Following examples illustrate the embodiments of this invention.

In the Examples, "part" shows part by weight and "equivalent" showsmolar equivalent of the beta-lactam starting material. Symbols "cis" and"trans" show relative position of amido and carboxylic substitutentsattaching to the side chain double bond. Physicochemical constants ofthe products are summarized in Tables in which IR shows cm⁻¹ value, NHRshows δ-value, and J value shows coupling constants in Hz scale. In NMRof a geometric isomer mixture, signals splitting into two or more areshown by chemical shifts separating with comma and splitting number and"X" before multiplicity mark.

Usually the reaction mixture is, if required after adding a solvent(e.g., water, acid, dichloromethane), washed, dried, and concentrated,and the product is separated. All concentrating are done in reducedpressure.

(Abbreviations) AOM=acetoxymethyl; BH=diphenylmethyl; Bu=butyl;BOC=t-butoxycarbonyl; Bzl=benzyl; Cbz=benzyloxycarbonyl; circle in ahetero ring of the structural formula=the ring is aromatic;exo=3,4-double bond position isomer in the 7-side chain acyl; Me=methyl;MEM=methoxyethoxmethyl; Ph=phenyl; PMB=p-methoxybenzyl;PNB=p-nitrobenzyl; and POM=pivaloyloxymethyl.

EXAMPLE 1 (Sodium Salt)

(1) A solution of carboxylic acid (1) in Table 2 (1 g) in aqueous 0.5%sodium hydrogen carbonate (6 ml) adjusted to pH 7 with hydrochloric acidis washed with ethyl acetate, desalted, and poured into a 10 ml vial.This is lyophilized conventionally to give the corresponding sodium salt(2) as powder.

(2) Similarly, to a suspension of carboxylic acid (I) (1 g) of Table 2in water is added aqueous sodium carbonate to make a solution of pH 6.5.The solution is desalted and poured into 10 ml vials, and lyophilized togive a sodium salt preparation same to above.

(3) The sodium salt (1 g) produced under sterile condition is dissolvedin sterile water (4 g) and is given twice a day orally or intravenouslyto a patient suffering from Staphylococcus aureus infection for treatingsaid disease.

(4) Each one of the carboxylic acids on Table 2 are dissolved in aqueoussodium hydrogen carbonate and assayed as the sodium salts for MIC by thestandard method of Japan Society of Chemotherapy to give values of 3.1to 0.2 microgram/ml against Streptococcus pyogenes C-203 and 0.8 to0.025 microgram/ml against Escherichia coli H.

EXAMPLE 2 (Amidation)

A 7-beta-amino compound (2) (1 equivalent) is treated with carboxylicacid corresponding to the 7-beta-side chain (3) or its reactivederivative to give amide (1), for a method as exemplified below:##STR8##

(1) In a mixture of dichloromethane (10 volumes),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.1 equivalents),N,N'-dicyclohexylcarbodiimide (1.1 equivalents), pyridine (1.5equivalents), and carboxylic acid (3) (1.1 equivalents), stirred for 1to 6 hours at 0° C. to room temperature.

(2) In a mixture of ethyl acetate (10 volumes), di-2-pyridyl disulfide(1.1 equivalents), triphenylphosphine (1.1 equivalents), and carboxylicacid (3) (1.1 equivalents), stirred for 2 to 6 hours at 10° to 50° C.

(3) In a mixture of dichloromethane (3 volumes),1,3,5-tripyridiniumtriazine trichloride (4 equivalents), and carboxylicacid (3) (1.1 equivalents), stirred for 1 to 5 hours at -10° to 10° C.

(4) In a mixture of carbon tetrachloride (30 volumes),4-methylmorpholine (1.5 equivalents), trisdiethylaminophosphine (1.1equivalents) and carboxylic acid (3) (1.1 equivalents), kept at -20° to10° C. for 1 to 5 hours.

(5) In a mixture of chloroform (10 volumes) and dimethoxyethane (10volumes), triethylamine (1.5 moles), and a mixed anhydride of carboxylicacid (3) and isobutoxyformic acid, stirred at a temperature between -5°to 10° C. over a 30 minutes and 6 hours time.

(6) In a mixture of ethyl acetate (10 volumes), 1,2-dichloroethane (10volumes), 4-methylmorpholine (1.5 equivalents), and the symmetricanhydride of carboxylic acid (3) (1.1 equivalents), refluxed for 10minutes to 2 hours.

(7) In a mixture of dichloromethane (10 volumes), pyridine (1.5equivalents), and mixed anhydride of carboxylic acid (3) andmethanesulfonic acid (1.1 equivalents), stirred for 1 to 3 hours atbetween -70° C. and room temperature.

(8) In a mixture of ethyl acetate (10 volumes), pyridine (1.5equivalents) and a mixed anhydride of diethyl hydrogen phosphate andcarboxylic acid (3) (1.5 equivalents), stirred at 0° C. to 10° C. for 1to 5 hours.

(9) In a mixture of ethyl acetate (10 volumes), dichloromethane (10volumes), N-methylmorpholine (1 equivalent), and mixed anhydride ofcarboxylic acid (3) and dichlorophosphoric acid (1.1 equivalents),stirred for 1 to 3 hours at 0° C. to room temperature.

(10) In a mixture of lutidine (1.5 equivalents), dichloromethane (10volumes), and the mixed anhydride (1.1 to 2 equivalents) of carboxylicacid (3) and monochlorophospheoric acid dimethylamide, stirred for 1 to4 hours at 0° to 30° C.

(11) In a mixture of dichloromethane (5 volumes), trifluoroaceticanhydride (1.5 equivalents), pyridine (3 equivalents), and carboxylicacid (3) (1.5 equivalents), stirred for 1 to 5 hours at 0° C. to roomtemperature.

(12) In a mixture of dichloromethane (10 volumes), bromide of diethylhydrogen phosphate (1.2 equivalents), 4-methylmorpholine (2.5equivalents), and carboxylic acid (3) (1.2 equivalents), stirred for 1to 3 hours at 0° C. to room temperature.

(13) Amine (2) having carboxy at position 4 of the cephem ring isdissolved in aqueous (10 volumes) sodium hydrogen carbonate (2.5equivalents). Carboxylic acid (3) chloride (1.1 equivalents) is dropwiseadded thereto. The mixture is kept at -5° C. to room temperature for 30minutes to 2 hours.

(14) Amine (2) having carboxy at position 4 of the cephem ring istreated with trimethylsilyl chloride and triethylamine (1.2 equivalentseach), and then treated with pyridine (4 equivalents) and carboxylicacid (3) chloride (1.1 equivalents) at -30° C. for between 30 minutesand 2 hours, and then the resulting silyl ester is hydrolyzed with acid.

(15) In a solution of picoline (4 equivalents) and carboxylic acid (3)chloride (1.2 equivalents) in dichloromethane (20 volume) stirred at 0°C. to -30° C. over 30 minutes and 2 hours.

(16) In a mixture of dimethylformamide (2 volumes) and ethyl acetate (10volumes), stirred with triethylamine (1.1 equivalents) and carboxylicacid (3) chloride (1.1 equivalents) at 0° C. to 20° C. for between 30minutes and 3 hours.

(17) In a mixture of dichloromethane (30 volumes), cyanuric chloride(1.1 equivalents), pyridine (4 equivalents), and carboxylic acid (3)(1.1 equivalents), stirred for 5 minutes to 2 hours at -30° C. to 10° C.

(18) In a mixture of dichloromethane (3 volumes), phosphorus oxychloride(1.1 equivalents), triethylamine (1.5 equivalents), and carboxylic acid(3) (1.1 equivalents), stirred for 20 minutes to 2 hours at -10° C. to10° C.

(19) Amine (2) is treated with trimethylsilyl chloride and an acidscavenger to obtain the corresponding N-trimethylsilyl compound, andthis is treated with phosphorus oxychloride (1.5 equivalents),carboxylic acid (3) (1.2 equivalents), and dimethylamiline (4equivalents) in dichloromethane (5 parts) for 30 minutes to 2 hours at0° C. to room temperature.

(20) in a mixture of dichloromethane (8 volumes), thionylchloride (1.5equivalents), pyridine (2.5 equivalents), and carboxylic acid (3) (1.1equivalents), stirred for 1 to 5 hours at -30° to 0° C.

(21) In a mixture of chloroform (3 volumes), toluene (1 volume),picoline (2 equivalents), oxalyl chloride (1 equivalent), and carboxylicacid (3) (1.1 equivalents), stirred for 10 minutes to 2 hours at -50° C.to 10° C.

(22) In a mixture of dichloromethane (20 volumes), pyridine (3equivalents), and benzotriazolyl ester of carboxylic acid (3) (3equivalents), stirred for 5 to 30 hours at 10° to 50° C.

(23) In a mixture of dichloromethane (20 volumes),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.5 equivalents) andcarboxylic acid (3) (2 equivalents), stirred at room temperature for 1to 15 hours.

(24) In a mixture of dioxane (10 volumes) and phthalimido ester ofcarboxylic acid (3) (2 equivalents), stirred for 2 to 8 hours at 10° to50° C.

(25) In a mixture of methyl isobutyl ketone (10 volumes) and succinimidoester of carboxylic acid (3) (1.5 equivalents), stirred for 2 to 9 at 0°to 40° C.

(26) In a mixture of carbonyldiimidazole (1.1 equivalents),tetrahydrofuran (10 volumes), dimethylacetamide (5 volumes), andcarboxylic acid (3) (1.1 equivalents), stirred for 1 to 5 hours at 0° C.to room temperature.

(27) In a mixture of dimethylformamide (5 volumes), dimethylamiline (1.3equivalents), carboxylic acid (3), and the Vilsmeyer reagent made fromdimethylformamide (1.1 equivalents), stirred at room temperature for 1to 5 hours.

(28) In a mixture of dichloromethane (10 volumes), dimethylformamide (5volumes), N,N'-dicyclohexylcarbodiimide (1.1 equivalents), picoline (1.2equivalents), and carboxylic acid (3) (1.1 equivalents), reacted for 2hours to 24 hours.

(29) To a solution of7-amino-3-(1-methyl-5-tetrazolyl)-thiomethyl-3-cephem-4-carboxylic aciddiphenylmethyl ester in dichloromethane (50 parts) containing2-(2-benzyloxycarbonamido-4-thiazolyl)-4-benzyloxycarbonyl-2-butenoicacid (1 equivalent) is added N,N'-dicyclohexylcarbodiimide (1equivalent). After stirring for 2 hours at room temperature, the mixtureis concentrated. The residue is triturated in ethyl acetate, filtered toremove solid, and purified by column chromatography to give7-[2-(2-benzyloxycarbonylamino-4-thiazolyl)-4-benzyloxycarbonyl-2-butenoylamino]-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylicacid diphenylmethyl ester. Yield: 90%

(30) To a solution of 7-amino-3-pyridiniomethyl-3-cephem-4-carboxylicacid chloride hydrochloride in a mixture of water (10 parts) and dioxane(15 parts) are added at 0° C. sodium hydrogen carbonate (2 equivalents),2-(2-benzyloxycarbonylamino-4-thiazolyl)-4-benzyloxycarbonyl-2-butenoicacid (1.2 equivalents), 1-hydroxybenzotriazole (1.2 equivalents),N,N'-dicyclohexylcarbodiimide (1.2 equivalents), and dioxane (5 parts)at 0° C. After stirring at 0° C. for 3.5 hours, the mixture is acidifiedwith 1N-hydrochloric acid (5 parts) and filtered. The filtrate andacetone (50 parts) washing of the solid are combined, purified by silicagel chromatography, and lyophilized to give7-[2-(2-benzyloxycarbonylamino-4-thiazolyl)-4-benzyloxycarbonyl-2-butenoylamino]-3-pyridiniummethyl-3-cephem-4-carboxylate.Yield: 50.8%.

EXAMPLE 3 (Carboxy-Deprotection)

(1) A solution of a t-butyl, p-methoxypenzyl, or diphenylmethyl ester ofTable 1 in a mixture of dichloromethane (0.3 to 3 parts),trifluoroacetic acid (0.3 to 3 parts), and anisole (0.5 to 5 parts) isstirred for 10 minutes to 3 hours at between -10° and 40° C. Thesolution is concentrated to remove the solvent and reagent. The residueis washed with benzene or ether to give the corresponding acid in 70 to90% yield.

(2) To a solution of a t-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl,or diphenymethyl ester listed on Table 1 in a mixture of dichloromethane(5 to 9 parts) and anisole (2 to 8 parts) is added aluminum chloride,tin tetrachloride, or titanium tetrachloride (3 to 12 equivalents) atbetween -10° and 10° C., and the mixture is stirred for 1 to 24 hours.The mixture is washed with diluted hydrochloric acid and water, driedand concentrated to give the corresponding free acid in 80 to 95% yield.t-Butoxycarbonylamino, N-t-butoxycarbonyl-N-methoxyethoxymethylamino, orbenzyloxycarbonylamino group when present, is deprotected to give aminogroup.

(3) To a solution of a t-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl,or dipehnylmethyl ester listed on Table 1 are added 90% formic acid (5to 6 parts) and anisole (2 3 parts). The mixture is stirred at 50° to60° C. for 1 to 4 hours to give the corresponding carboxylic acid in 40to 50% yield.

(4) To a solution of a p-nitrobenzyl ester of Table 1 in dichloromethane(60 parts) are added acetic acid (10 parts) and zinc powder (2 parts).After stirring for 2 hours at 0° C., the mixture is filtered to removesolid, diluted with water, and extracted with dichloromethane. Theextract solution is washed with water and extracted with aqueous sodiumhydrogen carbonate. The aqueous layer is washed with hydrochloric acidto pH 2, and extracted with dichloromethane. This organic layer iswashed with water, dried, and vacuum concentrated to give thecorresponding free acid in 60 to 80% yield.

(5) The same ester can be deesterified by shaking with hydrogen in thepresence of the same amount of 5% palladium charcoal in dioxane at roomtemperature for 2 hours.

(6) To a solution of7-[2-(2-benzyloxycarbonylamino-4-thiazolyl)-4-benzyloxycarbonyl-2-butenoylamino]-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylicacid diphenylmethyl ester in anisole (12 parts) is added aluminumchloride (9 equivalents). After stirring for 4 hours at 0° C., themixture is neutralized with aqueous 5% sodium hydrogen carbonate,filtered to remove solid, and washed with ethyl acetate. Aqueous layeris acidified with hydrochloric acid, washed with ethyl acetate, andpassed through a column of HP 20 or SP 207 (synthetic adsorbent producedby Mitsubishi Chemical K. K.). Adsorbed material is eluted with 80%methanol to afford7-[2-(2-amino-4-thiazolyl)-4-carboxy-2-butenoylamino]-3-(1-methyl-5-tetrazolyl)thiomethyl-3-cephem-4-carboxylicacid. Yield: 65%.

(7) To a suspension of7-[2-(2-benzyloxycarbonylamino-4-thiazolyl)-4-benzyloxycarbonyl-2-butenoylamino]-3-pyridinium-methyl-3-cephem-4-carboxylicacid in anisole (2 parts) is added a solution of aluminum chloride (9equivalents) in anisole (2 parts) at 0° C. After stirring for 3.5 hours,the mixture is acidified with 10% hydrochloric acid and washed withethyl acetate. Aqueous layer is passed through a column of Diaion HP-20.Adsorbed material is eluted with aqueous 5% acetone and the eluatelyophilized to give7-[2-(2-amino-4-thiazolyl)-3-carboxymethylacrylamido]-3-pyridiniomethyl-3-cephem-4-carboxylicacid. Yield: 55%.

(8) In a manner similar to that of above (1) to (7), a free carboxycompound of Table 2 are prepared from the correspondingcarboxy-protected compound of Table 1.

(9) To a solution of diphenylmethyl7beta-[2-(2-carbobenzoxyaminothiazol-4-yl)-4-allyloxycarbonyl-2-butenoylamino]-3-cephem-4-carboxylate(3.75 g) (5 mM) in dichloromethane (30 ml) are added 2-ethylhexanoate(1.5 molar equivalents), triphenylphosphine (0.5 equivalents), andtetrakistriphenylphosphine-palladium complex (125 mg). After stirringfor 1 hour at 25° C., the mixture is dilute with ether to separatediphenylmethyl7beta-[2-(2-carbobenzoxyaminothiazol-4yl)-4-sodiooxycarbonyl-2-butenoylamino]-3-cephem-4-carboxylatein 94% yield. This is suspended in water (10 parts) and acidified withaqueous 4% phosphoric acid to separate diphenylmethyl7beta-[2-(2-carbobenzoxyaminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylate.

EXAMPLE 4 (Amino Deprotection)

(1) A solution of a t-butoxycarbonylamino compound listed on Table 1 ina mixture of dichloromethane (0.3 to 3 parts), trifluoroacetic acid (0.3to 3 parts), and anisole (0.5 to 5 parts) is stirred for 10 minutes to 3hours at between -10° and 40° C. The solution is concentrated to removethe solvent and reagent. The residue is washed with benzene to give thecorresponding amino compound listed on Table 1 or 2 in 70 to 80% yield.

(2) To a solution of a t-butoxycarbonylamino, benzyloxycarbonylamino,methylbenzyloxycarbonylamino, methoxyethoxymethylamino, or trityl-aminocompound listed on Table 1 (1 part) in a mixture of dichloromethane (5to 9 parts) and anizole (2to 8 parts) is added aluminum chloride, tintetrachloride, or ticanium tetrachloride (3 to 12 equivalents) atbetween -10° and 10° C., and the mixture is stirred for 1 to 24 hours.The mixture is extracted with diluted hydrochloric acid and water, theaqueous layer is passed through a column of HP-20 absorbent to give thecorresponding free amino compound listed on Table 1 or 2 in 60 to 80%yield. A t-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl, ordiphenylmethyl ester group when present, is deprotected to give freecarboxy.

(3) To a solution of a chloroacetamido compound of Table 1 in a mixtureof tetrahydrofuran (15 parts) and methanol (15 parts) are added thioureaor N-methyldithiocarbamate (4 equivalents) and sodium acetate (2equivalents). after one night at room temperature, the mixture isconcentrated, diluted with ethyl acetate, washed with saline, dried, andconcentrated. The residue is chromatographed to give the correspondingamino compound.

(4) To a solution of a formamido, Schiff base, silylamino, ortritylamino compound listed on Table 1 in formic acid, acetic acid, orethanol (10 parts) is added 1 to 3N-hydrochloric acid (0.1 to 3 parts),and the mixture is stirred for 1 to 3 hours at room temperature. Thereaction mixture is concentrated, diluted with dichloromethane, washedwith aqueous sodium hydrogen carbonate and water, dried andconcentrated. The residue is purified in a conventional manner to givethe corresponding free amino compound listed on Table 1 or 2.

(5) To a solution of a benzyloxycarbonylamino compound listed on Table 1in a mixture of ethanol and ethyl acetate (30 parts: 1:1) is added 5%palladium charcoal (0.5 parts), and the mixture is shaken under hydrogenuntil the starting material is consumed. The reaction mixture isfiltered to remove solid and concentrated to give the correspondingamino compound listed on Table 1 or 2.

EXAMPLE 5 (Esterification) (R³ and/or R⁶ =diphenylmethyl)

(1 ) To a solution of compound (I) in which R³ and/or R⁶ is hydrogen ina mixture of dichloromethane and methanol (10 weights each) is addeddiphenyldiazomethane (2 equivalents). After stirring for 1 hour, themixture is washed with hydrochloric acid and water, dried, andconcentrated. The residue is crystallized from ethyl acetate to give thecorresponding diphenylmethyl ester.

(R³ and/or R⁶ =POM)

(2) To a solution of compound (I) wherein R³ and/or R⁶ is potassium inN,N-dimethylformamide (2 to 5 parts) is added iodomethyl pivalate (1 to2 equivalents) under ice-salt cooling. After 15 minutes to 2 hour'sstirring, the mixture is diluted with ethyl acetate, washed with icewater and aqueous sodium hydrogen carbonate, dried, and concentrated invacuum. The residue is recrystallized from ethyl acetate to give thepivaloyloxymethyl ester of the carboxylic acid of Table 3.

(3) The potassium salt of above section (2) is replaced by sodium saltto give the same products under the same condition.

(4) The pivaloyloxymethyl ester of above section (2) (250 mg), cornstarch (150 mg), and magnesium stearate (5 mg) are mixed, granulated,and encapsulated in a conventional manner. This capsule (2 to 3capsules) are given orally to treat a patient suffering from infectioncaused by sensitive E. coli. (R³ and/or R⁶ =ACN).

(5) In place of iodomethyl pivalate of above (2), iodomethyl acetate isused under the same reaction condition to give the correspondingacetoxymethyl ester of Table 3.

EXAMPLE 6 (Introduction of 3-substituents) (R⁵ =H)

(1) To a solution of a compound listed on Table 1 and havingmethanesulfonyloxy or chlorine as R⁵ in dichloromethane (13 parts) areadded acetic acid (10 part) and zinc powder (2.5 parts) and the mixtureis heated at 50° C. for 5 hours. The reaction mixture is filtered toremove solid, diluted with ethyl acetate, washed with dilutedhydrochloric acid, water, aqueous sodium hydrogen carbonate, and water,dried, and concentrated. The residue is purified by silica gelchromatography eluting with a mixture of benzene and ethyl acetate togive the corresponding compound listed on Table 1 or 2 having hydrogenas R⁵ in 50 to 80% yield.

(2) Above reaction (1) is carried out at room temperature for 5 to 10hours in the presence of a diluent isopropanol (4 parts) to give thesame product in 40 to 60% yield.

(3) To a solution of7beta-[2-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonylbut-2-enoylamino]-3-hydroxycepham-4-carboxylicacid diphenylmethyl ester sulfoxide in dichloromethane (13 parts) areadded pyridine (6 equivalents) and acetic anhydride (6 equivalents).After 13 hours' stirring at 0° C., the mixture is mixed withtriethylamine (3 equivalents) and stirred for 24 hours. The reactionmixture is washed with water, aqueous sodium hydrogen carbonate, andwater, dried, and concentrated to give7beta-[2-(2-benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoylamino]-3-cephem-4-carboxylicacid dipehnylmethyl ester sulfoxide in 40 to 60% yield.

(R⁵ =cyanomethylthiomethyl)

(4) In the manner as given in Preparation B-4 a compound havingbromomethyl as R⁵ is treated with sodium cyanomethyl mercaptide at -65°C. to 70° C. for 2 hours to give the corresponding compound listed onTable 1 having cyanomethylthiomethyl as R⁵ in 50 to 60% yield.

EXAMPLE 7 (Sulfoxide Reduction)

In a manner similar to that of Preparation B-4 (2) using the same ratioof the reagent and solvents, the corresponding sulfoxide is reduced togive the cephem (sulfide) compounds of Table 1.

EXAMPLE 8 (Double Bond Migration)

A solution of7beta-[2-(2-t-butoxycarbonylaminothiazole-4-yl)-4-benzyloxycarbonyl-2-butenoylamino]-3-chloro-2-cephem-4-carboxylicacid diphenylmethyl ester is reduced according to the method of Example6 (1) to induce concomitant double bond migration affording7beta-[2-(2-aminothiazolyl-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylicacid diphenylmethyl ester in 53% yield.

EXAMPLE 9 (Amine Salt)

To a solution of an amino compound listed on Table 2 in dilutedhydrochloric acid is added acetonitrile. The precipitated material iscollected by filtration to give the corresponding hydrochloric acidaddition salt in good yield.

PREPARATION A (Preparation of Carboxylic Acids Preparation A-12-(2-Benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonyl-2-butenoicacid (3) ##STR9##

(1) A solution of formylacetate (1) andbenzyloxycarbonylmethylidenetriphenylphosphorane (1.3 equivalents) indioxane or toluene (8 parts) is stirred for 1 to 6 hours at 80° to 120°C. After cooling, the mixture is concentrated, and the residue ispurified by silica gel chromatography to give propenedicarboxylate (2).Yield: 85%. This is a mixture of 34% cis and 53% trans geometric isomerswhich can be separated after repeated chromatography.

IR (CHCl₃) ν: 3410, 1730 cm⁻¹ (trans).

IR (CHCl₃) ν: 3400, 1730 cm⁻¹ (cis).

(2) To a solution of this produce (2) in dichloromethane (10 parts) areadded anisole (2 parts) and trifluoroacetic acid (2 parts). Afterstirring for 2 hours, the reaction mixture is concentrated, and theresidue washed with a mixture of ether and hexane to give monobenzylester of the dicarboxylic acid (3). Yield: 89%. These geometric isomerscan be separated by chromatographs.

NMR (CDCl₃ --CD₃ OD): δ3.51 (d, J=7 Hz, 2H), 5.13 (s, 2H), 5.26 (s, 2H),7.06 (s, 1H), 7.0-7.5 (m, 11H) (trans).

NMR (CDCl₃ --CD₃ OD): δ3.73 (d, J=7 Hz, 2H), 5.13 (s, 2H), 7.10 (s, 1H),7.0-7.5 (m, 11H) (cis).

In a manner similar to that of Preparation A-1, a butenoic acid diesterlisted on Table 4 is prepared from the corresponding formylacetate usingthe same ratios of reactants and solvents at the same temperature forthe same reaction time. The obtained ester is, if required, totally orpartially deesterified using a conventional reagent, e.g., sodiumhydroxide for alkyl esters and a Lewis acid (e.g., aluminum, titanium,or tin halide) for t-alkyl or aralkyl esters, to give free acids.

Preparation A-22-(2-Benzyloxycarbonylaminothiazol-4-yl)-3-benzyloxycarbonyl-2-propenoicacid (3). ##STR10##

(1) A solution of 2-oxoacetate (1) andbenzyloxycarbonylmethylidenetriphenylphosphorane (1.25 equivalents) intoluene or dioxane (10 parts) is refluxed for 1 to 3 hours. The mixtureis concentrated and the residue purified by silica gel chromatography togive diester (2). Yield: 95%.

NMR (CDCl₃)δ: 5.12 (s, 4H), 7.00 (s, 1H), 7.07 (s, 1H), 7.1-7.5 (m,21H).

This product is a mixture of cis-trans isomers at the double bond.

(2) The produce (2) is dissolved in dichloromethane (7 parts) and mixedwith trifluoroacetic acid (1 part) and anisole (1 part). After stirringfor 7 hours at 0° C., the mixture is concentrated and triturated in amixture of ether and hexane and then in a mixture of ether and methanolto give monoester (3), trans isomer. Yield: 83%.

IR (Mujol)ν: 1730, 1710, 1695 cm⁻¹.

NMR (CDCl₃ +CD₃ OD)δ: 5.17 (s, 2H), 5.27 (s, 2H), 7.07 (s, 1H), 7.2-7.5(m, 11H) ppm.

(3) This trans isomer (3) is dissolved in tetrahydrofuran (10 parts) andmixed with phosphorus pentachloride (1.12 equivalents). After stirringfor 2 hours at 0° C., the mixture is neutralized with aqueous 5% sodiumhydrogen carbonate (80 ml) and stirred at room temperature. Separatedcrystals are collected by filtration, washed with ethyl acetate andwater, suspended in water, acidified with hydrochloric acid, andextracted with ethyl acetate. The extract is washed with water, dried,and concentrated. The residue is crystallized from a mixture of etherand hexane to give monoester (3), cis isomer. Yield: 47%. mp. 144°-146°C.

IR (CHCl₃)ν: 3410, 1720 cm⁻¹.

NMR (CDCl₃ +CD₃ OD)δ: 5.18 (s, 2H), 5.23 (s, 2H), 6.62 (s, 1H), 7.15 (s,1H), 7.32 (s, 5H), 7.35 (s, 5H) ppm.

Preparation A-32-(2-Benzyloxycarbonylaminothiazol-4-yl)-5-benzyloxycarbonyl-2-pentenoicacid (5) ##STR11##

(1) A mixture of 4-chloroacetoacetic acid benzhydryl ester (1) (6.95 g),aldehyde (2) (3.9 g), benzene (35 ml), piperidine (0.79 ml), and aceticacid (0.24 mg) is heated at 50° C. for 3 hours. The mixture is washedwith water, aqueous saturated sodium hydrogen carbonate, water,0.5N-hydrochloric acid, and water, dried over magnesium sulfate, andconcentrated. The residue is subjected to silica gel chromatography(eluting with benzene) to give a mixture of cis and trans (1:1) isomersof the product (3) (5.7 g).

(2) To a solution of this produce (3) in ethanol (30 ml) is addedthiourea (1.1 g). After heating at 50° C. for 2 hours, the mixture iswashed with aqueous saturated sodium hydrogen carbonate andconcentrated. The residue is dissolved in dichloromethane (20 ml) andmixed with pyridine (0.536 ml) and benzyl chloroformate (0.757 ml) at 0°C. After 1.5 hours' stirring at 0° C., the mixture is washed with water,dried over magnesium sulfate, and concentrated. The residue is purifiedby silica gel chromatography (eluting with benzene-ethyl acetate (20:1)mixture) to give aminothiazole ester (4), cis isomer (467 mg) and transisomer (600 mg).

(cis isomer)=IR (CHCl₃)ν: 3400, 1720, 1540, 1440, 1385, 1280, 1160 cm⁻¹.

(trans isomer)=IR (CHCl₃)ν: 3400, 1720, 1540, 1440, 1385, 1280, 1160cm⁻¹.

(3) To the isomers of aminothiazole ester (4) respectively are addeddichloromethane, anisole (1 part), and trifluoroacetic acid (2 parts).After 2 hours stirring at 0° C., the mixture gives each isomer of thecorresponding dicarboxylic acid monobenzyl ester (5).

Preparation A-42-(2-Benzyloxycarbonylaminothiazol-4-yl)-6-benzyloxycarbonyl-2-hexenoicacid (5) ##STR12##

(1) A solution of ester (1) (7 g), aldehyde (2) (4.8 g), piperidine(0.15 ml), and acetic acid (0.3 ml) in benzene (40 ml) is heated at 50°C. for 3 hours. The mixture is washed with water, aqueous saturatedsodium hydrogen carbonate, 0.5 N hydrochloric acid, and water, driedover magnesium sulfate, and concentrated.

(2) Resulting residue (3) (6.5 g) is dissolved in ethanol (35 ml), mixedwith thiourea, and heated at 50° C. for 2 hours. The mixture is washedwith aqueous saturated sodium hydrogen carbonate and concentrated. Theresidue is dissolved in dichloromethane (20 ml), mixed with pyridine(0.754 ml) and benzyl chloroformate (1 ml), and stirred at 0° C. for 1.5hours. The reaction mixture is washed with water, dried, andconcentrated. The residue is separated by silica gel chromatography(eluting with benzene-ethyl acetate (20:1) mixture) to give thiazoleester (4) [trans isomer (470 mg) and trans-cis (1:1) mixture (1.17 gl)].

(trans-Thiazole ester (4)): IR (CHCl₃)ν: 3400, 3000, 1720, 1540, 1440,1370, 1280, 1150 cm⁻¹.

(cis-Thiazole ester (4)): IR (CHCl₃)ν: 3400, 3000, 1720 1540, 1440,1370, 1280, 1150 cm⁻¹.

(3) Thiazole ester (4) (470 mg) as produced above (1) is dissolved indichloromethane (15 ml), mixed with anisole (0.611 ml) andtrifluoroacetic acid (1.22 ml), and stirred at 0° C. for 2 hours. Afterconcentrating to dryness, the mixture is triturated in a mixture ofether and hexane (1:1) to give thiazolecarboxylic acid (5) 336 mg).

Preparation A-52-(5-Benzyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-4-benzyloxycarbonyl-2-butenoicacid (7) ##STR13##

(1) Amine (1) (6 g) is amidated with benzyl chloroformate (1.2equivalents) in dichloromethane (120 ml) containing pyridine (2.5equivalents) at 0° C. for 2 hours to give carbamate (2) (11.2 g). mp.157°-158° C. Yield: 94.6%.

(2) To a solution of diisobutylamine (25.2 ml) in tetrahydrofuran (125ml) cooled at -30° C. to -5° C. is added 1.6 N n-butyllithium hexanesolution (112.3 ml) over 21 minutes period. After 1 hour 20 minutes'stirring at 0° C., the mixture is mixed with a solution of carbamate (2)(11.2 g) in tetrahydrofuran (150 ml) at -68° C. to -64° C. over 1 hour20 minutes, and stirred at the same temperature for 3 hours. This isquenched with dry ice (200 g) and warmed gradually up to -5° C. Thereaction mixture is diluted with water (150 ml), washed with ethylacetate, acidified with 2N-hydrochloric acid to pH 2, and extracted withdichloromethane. The extract solution is washed with water, dried,concentrated, and diluted with ether to afford acetic acid (3) (6.33 g).mp. 172°-173° C.

(3) To a solution of acetic acid (3) (7 g) in methanol (200 ml) is addeddiphenyldiazomethane until none of the acetic acid (3) is detectable.The mixture is concentrated to give Ester (4). mp. 144°-146° C.

(4) To a solution of ester (4) (4.1 g) and diphenylmethyl formate (3.03g) in tetrahydrofuran (41 ml) cooled at 0° C. is added 60% sodiumhydride (1.1 g). After 2 hours 20 minutes stirring at 60° C., themixture is diluted with water, acidified with 2N-hydrochloric acid, andextracted with ethyl acetate. The extract is washed with water, dried,and concentrated to give aldehyde (5) (2.76 g). Yield: 63.5%.

IR (CHCl₃)ν: 3140, 1720, 1610, 1540, 1280, 1080 cm⁻¹.

(5) A solution of aldehyde (5) (781 mg) andbenzyloxycarbonylmethylidenephosphorane (985 mg) in dioxane (17 ml) isrefluxed for 3 hours. The mixture is concentrated to give acrylate (6)(631 mg). Yield: 63.5%. A cis/trans (4:6) mixture.

IR (CHCl₃)ν: 3150, 1730, 1545, 1280 cm^(-l).

(6) To a solution of acrylate (6) (309 mg) in dichloromethane (4.5 ml)are added anisole (0.3 ml) and trifluoroacetic acid (0.6 ml). After 1hour's stirring at room temperature, the mixture is diluted with hexaneto give half ester (7) (171 mg). Yield: 75.7%. This is a cis/trans(1:6.45) mixture.

IR (CHCl₃)ν: 1730, 1621, 1540, 1280 cm⁻¹.

Preparation A-62-(2-Benzyloxycarbonylaminothiaxol-4-yl)-3-chloro-3-benzyloxycarbonyl-2-propenoicacid (3) ##STR14##

(1) A solution of ketone (1) (472 mg) andbenzyloxycarbonylchloromethylenetriphenylphosphorane (467 mg) in benzene(5 ml) is heated at 60° C. for 30 minutes and concentrated. The residueis crystallized from a mixture of ether and pentane to givechloroethylene (2) (393 mg). Yield: 61%.

(2) A solution of chloroethylene (2) (270 mg) in a mixture of anisole (2parts) and trifluoroacetic acid (1 part) is let stand for 15 minutes andconcentrated to give half ester (3) (190 mg). Yield: 95%.

Preparation A-72-(2-Benzyloxycarbonylaminothiazol-4-yl)-3-benzyloxycarbonylmethylthio-3-chloro-2-propenoicacid (4) ##STR15##

(1) Ketone (1) and dichloromethylidenetriphenylphosphorane are reactedin a manner as described in Japanese Patent Application Kokai 57-67581to give dichloroethylene (2).

(2) To an ice cold solution of dichloroethylene (2) (395 mg) inN,N-dimethylformamide (3 ml) are added benzyl thioglycolate (200 mg) andtriethylamine (153 mg) under nitrogen. After stirring for 45 minutes,the mixture is diluted in ethyl acetate, washed with water, dried, andconcentrated. The residue is purified by chromatography to givethioether (3) (326 mg). Yield: 64%.

(3) A solution of thioether (3) in a mixture of trifluoroacetic acid (2parts) and anisole (2 parts) is let stand for 30 minutes andconcentrated to give half ester (4). Yield: 88%.

Preparation A-82-(2-Benzyloxycarbonylaminothiazol-4-yl)-3-chloro-6-benzyloxycarbonyl-2-hexenoicacid (4) ##STR16##

(1) To a suspension of (4-carboxybutyl)triphenylphosphonium bromide (887mg) in tetrahydrofuran (3.5 ml) is added 1M-lithiumbistrimethylsilylamide (4.2 ml). After 15 minutes' stirring at roomtemperature, this solution is dropwise added to a suspension ofiodobenzenedichloride (605 mg) in tetrahydrofuran at -78° C. After 10minutes at -78° C., lithium bistrimethylsilylamide (2.2 ml) is added tothe mixture. To this solution is added a solution of ketoester (1) (378mg) in tetrahydrofuran (2 ml). The mixture is stirred at -78° C. for 10minutes and at room temperature for 1 hour, diluted with dilutedhydrochloric acid, and extracted with ethyl acetate. The extractsolution is dried and concentrated. The residue is purified by silicagel chromatography (eluting with dichloromethane and ethyl acetate (1:1)mixture) to give vinylcarboxylic acid (2) (250 mg).

IR (CHCl₃) ν: 1715, 1540 cm⁻¹.

(2) Esterification of vinylcarboxylic acid (2) (353 mg) with oxalylchloride and benzyl alcohol in the presence of pyridine in aconventional manner gives vinyl ester (3) (305 mg).

NMR (CDCl₃) δ:1.85-3.00 (m, 6H), 5.07 (s, 2H), 5.25 (s, 2H), 6.48 (s,1H), 7.05 (s, 1H), 7.10-7.55 (m, 20H) ppm.

(3) Stirring a mixture of vinyl ester (3) (275 mg), trifluoroacetic acid(0.5 ml), and anisole (1 ml) for 15 minutes at room temperature giveshalf ester (4) (95 mg).

NMR (CDCl₃ +CD₃ OD) δ: 1.80-3.00 (m, 6H), 5.09 (s, 2H), 5.26 (s, 2H),6.85 (s, 1H), 7.05-8.00 (m, 10H) ppm.

Preparation A-92-[2-(N-Methoxyethoxymethyl-N-benzyloxycarbonylamino)triazol-4-yl]-3-chloro-5-benzyloxycarbonyl-2-pentenoicacid (6) ##STR17##

(1) To a solution of aminoester (1) (115 mg) in N,N-dimethylformamide (1ml) are added potassium carbonate (45 mg) and methoxyethoxymethylchloride (0.043 ml). After stirring at room temperature for 1.5 hours,the mixture is diluted with iced hydrochloric acid and extracted withethyl acetate. The extract is washed with water, dried, andconcentrated. The residue is purified by silica gel chromatography togive methoxyethoxymethylamino ester (2).

Yield: 74%.

NMR (CDCl₃) δ: 3.25 (s, 3H), 3.77 (s, 2H), 5.28 (s, 2H), 5.55 (s, 2H),6.68 (s, 1H) ppm.

(2) To a solution of 0.3M-lithium bistrimethylsilylamide intetrahydrofuran (1.4 ml) is added a solution of methoxyethoxymethylaminoester (2) (100 mg) in tetrahydro-furan (1 ml) at -78° C. under nitrogen.After stirring for 15 minutes, a solution of succinic anhydride (22 mg)in tetrahydrofuran (0.5 ml) is added to the solution. After 50 minutes'stirring at -78° C., the reaction mixture is acidified with4N-hydrochloric acid (0.5 ml) and extracted with dichloromethane. Theextract is washed with water, dried, and concentrated. The residue ispurified by silica gel chromatography to give ketoester (3) (64%) andamino ester (1) (24 %).

NMR (CDCl₃) δ: 3.27 (s, 3H), 5.32 (s, 2H), 5.50, 5.65 (2×s, 2H), 9.4(brs, 1H) ppm.

(3) To a solution of keto ester (3) (541 mg) in benzene (5 ml) is addeda 0.485M-solution (1.81 ml) of sodium methoxide in methanol. Afterstirring for 5 minutes, the mixture is concentrated. The residue isdissolved in N,N-dimethylformamide (5 ml), mixed with benzyl bromide(0.149 ml), stirred for 5.5 hours at room temperature, let standovernight, and subjected to usual work-up and silica gel chromatographyto afford ketodiester (4). Yield: 33%.

NMR (CDCl₃) δ: 3.26 (s, 3H), 5.05 (s, 2H), 5.32 (s, 2H), 5.55, 5.63(2×s, 2H) ppm.

(4) to a solution of triphenylphosphine (284 mg) in tetrahydrofuran (4ml) cooled at -15° C. are added a 0.85 M solution of chlorine in carbontetrachloride (1.27 ml), triethylamine (0.152 ml), and a solution ofketodiester (4) (160 mg) in tetrahydrofuran (2 ml). The mixture iswarmed to room temperature, stirred for 6.5 hours, subjected to usualwork-up, and silica gel chromatography to give chlorodiester (5). Yield:67%.

This product is a mixture of cis and trans (1:1) geometric isomers.

IR (CHCl₃) ν: 1740 cm⁻¹.

(5) To an ice cold solution of chlorodiester (5) (109 mg) in anisole (1ml) is added trifluoroacetic acid (0.3 ml). After stirring at roomtemperature for 1 hour, the mixture is concentrated, and the residue ispurified by silica gel chromatography to give chloromonoester (6)trifluoroacetate salt 112 mg). This product is a mixture of cis andtrans (1:1) geometric isomers.

IR (CHCl₃) ν: 3350, 1720, 1680 cm⁻¹.

Preparation A-10

2-(5-Benzyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-3-benzyloxycarbonyl-2-propenoicacid (4) ##STR18##

(1) To a solution of ester (1) (1.012 g) in dioxane (10 ml) is addedselenium dioxide (0.66 g). After stirring for 2 hours at 100° C., themixture is filtered. The filtrate is concentrated. The residue isdissolved in ether and purified by silica gel chromatography (elutingwith a hexane-acetone (3:2) mixture) to give ketoester (2) (1.025 g).Yield: 98.3%.

IR (Nujol) ν: 3380, 1720, 1240, 1085 cm⁻¹.

(2) A solution of ketoester (2) (1.025 g) andtriphenylphosphoranilideneacetic acid benzyl ester (1.06 g) in dioxane(20 ml) is stirred at 100° C. for 2 hours and concentrated. The residueis purified by silica gel chromatography (eluting with acetone-hexane(3:1 to 3:2) mixture) to give diester (3) (1.24 g). Yield: 93%. mp.173°-174° C.

(3) To a solution of diester (3) (348 mg) in dichloromethane (4.7 ml)are added anisole (0.35 ml) and trifluoroacetic acid (0.76 ml). Afterstirring for 1 hour at room temperature, the mixture is concentrated andwashed with ether to give cis-monoester (4a) (147 mg). Yield: 58.3%. mp.201°-202° C. The washing is concentrated, washed with hexane, andcrystallized from a mixture of ether and hexane to give trans-monoester(4b) (98 mg). Yield: 38.9%. mp. 155°-156° C.

Preparation A-11

2-(2-t-Butoxycarbonylaminothiazol-4-yl)-4-methyl-4-benzyloxycarbonyl-2-pentenoicacid (3) ##STR19##

To a solution of acetate (1) (628 mg) in tetrahydrofuran (16 ml) coolingat -50° C. is added potassium t-butoxide (282 mg). After stirring for 5minutes, the mixture is mixed with benzyl 2-formyl-2,2-dimethylacetate(0.32 ml), stirred for 20 minutes, warmed to room temperature in 5minutes, neutralized with 10% hydrochloric acid, and extracted withethyl acetate. The extract is washed with saline, dried, andconcentrated. The residue is dissolved in benzene (10 ml), mixed withDBU (0.36 ml), stirred at room temperature for 4 hours, neutralized with10% hydrochloric acid, washed with water, dried, concentrated, dissolvedin benzene (10 ml), mixed with aqueous sodium sulfite (250 mg) solution(10 ml), and stirred for 24 hours. Benzene layer is washed with water,dried, concentrated, and purified by silica gel chromatography to givediester (2), cis isomer (431 mg: 59% yield) and trans isomer (158 mg;yield: 22%).

IR (CHCl₃) ν: 3410, 1725 cm⁻¹ (cis isomer).

IR (CHCl₃) ν: 3400, 1720 cm⁻¹ (trans isomer).

(2) To a solution of diester (2), cis isomer (431 mg), indichloromethane (8 ml) is added a mixture of anisole (1.2 ml) andtrifluoroacetic acid (1.2 ml). After stirring at 0° C. for 3 hours, themixture is concentrated and purified by silica gel chromatography togive cis-isomer of monoester (3) (242 mg). Yield: 77%. mp 158°-160° C.(decomp. recrystallized from benzene).

(3) To a solution of diester (2), trans isomer (237 mg), indichloromethane (4 ml) is added a mixture of anisole (0.6 ml) andtrifluoroacetic acid (0.6 ml). After stirring at 0° C. for 3.5 hours,the mixture is concentrated and purified by silica gel chromatography togive trans-isomer of monoester (3) (98 mg). Yield: 57%. mp. 175°-177° C.(decomp., recrystallized from benzene).

Preparation A-12

2-(2-t-Butoxycarbonylaminothiazol-4-yl)-3-t-butoxycarbonylmethoxy-2-propenoicacid (7) ##STR20##

(1) To a suspension of acetic acid (1) (11 g) in dichloromethane (120ml) is added triethylamine (90 ml). The mixture is cooled at -78° C.,mixed with 2,2,2-trichloroethyl chloroformate (4.87 ml) andN,N-dimethylaminopyridine (432 mg), stirred at 0° C. for 10 minutes andat room temperature for 2 hours, diluted with ethyl acetate, washed withwater, dried, and concentrated. The residue is purified by 10% aqueoussilica gel chromatography (eluting with a benzene-ethyl acetate (9:1)mixture) to give trichloroethyl ester (2) (9.10 g). Yield: 66%.

IR (CHCl₃) ν: 3400. 1760, 1720, 1150 cm⁻¹.

(2) To a suspension of sodium hydride (2.88 g) in tetrahydrofuran (80ml) is dropwise added a solution of trichloroethyl ester (2) (9.10 ) and2,2,2-trichloroethyl formate (6.21 g) in tetrahydrofuran (34 ml). Afterstirring at room temperature for 2 hours, the mixture is diluted withethyl acetate, acidified with acetic acid (5.3 ml), washed with watr,dried, and concentrated. The residue is crystallized from petroleumether to give formylester (3) (4.49g). Yield: 46%.

IR (CHCl₃) ν: 3420. 1735, 1620 cm⁻¹.

(3) To an ice cold solution of formylester (3) (4.49 g) inN,N-dimethylformamide (40 ml) is added 60% sodium hydride (426 mg). Themixture is stirred until gas evolution ceases, mixed witht-butylbromoacetate (3.15 g), kept at room temperature overnight,diluted with ethyl acetate, washed with saline, dried, concentrated, andpurified by silica gel chromatography (eluting with a benzene-ethylacetate (19:1 to 2:1 ) mixture) to give diester (4) (3.03 g). Yield:53%.

IR (CHCl₃) ν: 3400, 1723, 1630, 1150, 1120 cm⁻¹.

(4) To a solution of diester (4) (3.03 g) in tetrahydrofuran (30 ml) areadded benzenethiol (0.70 ml) and triethylamine (0.79 ml). The mixture isstirred at room temperature for 3.5 hours, concentrated, and purified bysilica gel chromatography (eluting with benzene-ethyl acetate (9:1 to8:2) mixture) to give phenylthiopropionate (5) (3.36 g). Yield: 92%.

The product is 7:3 mixture of the two geometric isomers.

IR (CHCl₃) ν: 3400, 1750, 1725, 1155, 1120 cm⁻¹.

(5) To a solution of phenylthiopropionate (5) (3.15 g) indichloromethane (35 ml) cooled at -40° C. is added m-chloroperbenzoicacid (80%, 1.07 g). The mixture is stirred at -40° C. for 10 minutes andat room temperature for 10 minutes, diluted with ethyl acetate, stirredwith aqueous 2% sodium hydrogen sulfite, and stirred at room temperaturefor 5 minutes.

The organic layer is taken, washed with aqueous 5% sodium hydrogencarbonate and saturated saline, dried, concentrated, dissolved inbenzene (150 ml), and refluxed for 5 minutes. The mixture is washed withaqueous 5% sodium hydrogen carbonate and saturated saline, dried,concentrated, and purified by silica gel chromatography (eluting with abenzene-ethyl acetate (9:1 to 1:1) mixture) to give diester (6) (1.13g). Yield: 45%.

IR (CHCl₃) ν: 3420, 1730, 1620, 1540, 1153, 1140 cm⁻¹.

(6) To a solution of diester (6) (0.80 g) in acetic acid (8 ml) is addedzinc powder (2.0 g). After stirring at room temperature for 1 hour, themixture is diluted with dichloromethane, mixed with 2N-hydrochloricacid, stirred for 10 minutes at room temperature, filtered to removesolid, and the organic layer is taken. This is washed with water, dried,and concentrated to give Z-isomer of monoester (7) (605 mg). Yield:100%.

IR (CHCl₃) ν: 3400, 3550-2500, 1725, 1620, 1150 cm³¹ 1.

E-isomer of monoester (7) (750 mg) is recovered from the mother liquor.Yield: 30%.

IR (KBr) ν: 3420, 1742, 1710, 1610, 1130 cm⁻¹.

Preparation A-132-(2-Benzyloxycarbonylaminothiazol-4-yl)-4-benzyloxycarbonylpentenoicacid (3) ##STR21##

(1) A solution of hydroxymethylene (1) (1.46 g) inbenzyloxycarbonylethylidenetriphenylphosphorane (2.5 g) in toluene (20ml) is stirred at 80° C. for 19 hours and at 110° C. for 4 hours, andthen concentrated. The residue is purified by silica gel chromatographyto give diester (2) (0.808 g). Yield: 43%.

NMR (CDCl₃) δ: 1.15 (d, J=7 Hz, 1.5H), 1.71 (s, 1.5H), 4.90 (d, J=9 Hz,0.5H), ppm.

(2) To a solution of diester (2) in dichloromethane (20 ml) are addedanisole (3 ml) and trifluoroacetic acid (3 ml). After stirring at roomtemperature for 3 hours, the mixture is concentrated and triturated in amixture of hexane and ether to give monoester (3) (508 mg). Yield: 85%.

IR (CHCl₃) ν: 3400, 1725 cm⁻¹.

Preparation A-14 2-(Thiazol-4-yl)-4-benzyloxycarbonyl-2-butenoic acid(3) ##STR22##

(1) To a solution of formylester (1) (11.5 g) in benzene (220 ml) isadded benzyloxycarbonylmethylidenephosphorane (19.5 g). After refluxingfor 7 to 10 hours, the mixture is concentrated to a half to a thirdvolume and purified by silica gel chromatography (eluting with abenzene-ethyl acetate (30:1) mixture) to give diester (2) (15.5 g).Yield 97%. The product is a mixture of cis and trans geometric isomers.

IR (CHCl): 1720 cm. (2) To a solution of diester (2) (15.0 g) indichloromethane (150 ml) is added trifluoroacetic acid (32 ml) at 0° C.After stirring at room temperature for 1.5 hours, the mixture isconcentrated. The residue is stirred in hexane, diluted with ethylacetate, and extracted with saturated aqueous sodium hydrogen carbonate.The extract is acidified with 10% hydrochloric acid to pH 3 to 4 andextracted with ethyl acetate. The extract is dried, concentrated, andtriturated in a mixture of ether and hexane (1:1) to give monoester (3).Yield: 55%. This product is a mixture of cis and trans (1:1) geometricisomers.

NMR (CDCl₃ -CD₃ OD) δ: 3.53, 3.76 (d, J=8 Hz, 2H), 5.13, 5.15 (2×s, 2H),7.23 , 7.38 (2×t, J=8 Hz, 1H), 7.35 (s, 5H), 7.57, 7.61 (d, J=2 Hz, 1H),8.79, 8.82 (d, J=2 Hz, 1H) ppm.

Preparation A-152-(3-t-Butoxycarbonylamino-5-isoxazolyl)-4-benzyloxycarbonyl-2-butenoicacid (7) ##STR23##

(1) A solution of 3-amino-5-methylisoxazole (1) (56 g) indi-t-butylpyrocarbonate is stirred at 105°-110° C. for 17 hours. Themixture is concentrated and diluted with ether and water. The organiclayer is taken, washed with water, diluted hydrochloric acid, water, andsaline, dried, and concentrated. The residue is washed with petroleumether to give t-butoxycarbonylamine (2) (75 g). mp 108°-109° C.

(2) To a solution of diisopropylamine (23.4 ml) under nitrogen intetrahydrofuran (90 ml) cooled at -20° C. is added n-butyllithium(1.6N-hexane solution 125 ml). After stirring for 15 minutes, themixture is cooled to -78° C., mixed with a solution oft-butoxycarbonylamine (2) (8.3 g) in tetrahydrofuran (40 ml) over 2minutes period, stirred for 1 hour, quenched with dry-ice (20 g), andconcentrated. The residue is dissolved in water, washed with ether,acidified with hydrochloric acid under ice cooling, and extracted withethyl acetate. The extract is washed with water, dried, andconcentrated. The residue is washed with ether to give acetic acid (3)(4.35 g). mp 173°-174° C. (decomp.).

(3) To a solution of acetic acid (3) in dichloromethane (200 ml) isadded triethylamine (8.63 ml) at 0° C. This is cooled to -78° C., mixedwith trichloroethyl chloroformate (13.1 g) and 4-dimethylaminopyridine(0.76 g), and stirred for 15 minutes. The mixture is warmed to roomtemperature, kept overnight, concentrated, diluted with water, andextracted with ethyl acetate. The extract is washed with dilutedhydrochloric acid, aqueous sodium hydrogen carbonate, water, and saline,concentrated, and purified by silica gel chromatography (eluting withbenzene-ethyl acetate (3:1) mixture) to give trichloroethylester (4) (19g). mp 146°-147° C.

(4) To a suspension of 60% sodium hydride 6.72 g) in tetrahydrofuran(220 ml) at -30° to -10° C. is added a solution of Trichloroethylester(4) and trichloroethyl formate (14.4 ml) in tetrahydrofuran (100 ml)over a 40 minutes period. After 1.5 hour's stirring, the mixture ispoured into iced hydrochloric acid and extracted with ethyl acetate. Theextract is washed with water and saline, dried, concentrated, and washedwith petroleum ether to give hydroxymethylidene compound (5) (17.45 g).mp >210° C.

(5) A solution of hydroxymethylidene compound (5) (8.06 g) andbenzyloxycarbonylmethylidenetriphenylphosphorane (11.1 g) in dioxan (350ml) is stirred at 55° C. for 9 hours. The mixture is concentrated,dissolved in water and ethyl acetate, washed with diluted hydrochloricacid, aqueous sodium hydrogen carbonate, water, and saline, dried,concentrated, and purified by silica gel chromatography (eluting with amixture of benzene and ethyl acetate (1:0 to 15:1) to give diester (6)(6.35 g).

IR (CHCl₃) ν: 3410, 2950, 1735, 1607, 1585 cm⁻¹.

(6) To a solution of diester (6) (1.85 g) in dichloromethane (20 ml) isadded zinc (5 g) and acetic acid (20 ml) at 0° C. After 40 minutesstirring, the mixture is poured into dichloromethane and dilutedhydrochloric acid, filtered to remove solid, and extracted withdichloromethane. The extract is washed with water and saline, dried,concentrated, and purified by silica gel chromatography (eluting with abenzene-ethyl acetate (3:1) mixture) go give monocarboxylic acid (7)(0.25 g).

IR (KBr) ν: 3400, 3250, 2960, 1736, 1618 cm⁻¹.

Preparation A-16 2-Phenyl-4-benzyloxycarbonyl-2-butenoic acid (3)##STR24##

(1) To a solution of 2-formylphenylacetic acid diphenylmethyl ester (1)(1.94 g) in dioxane (20 ml) is addedbenzyloxycarbonylmethylidenetriphenylphosphorane (3.16 g) at roomtemperature. After stirring at 60° to 65° C. for 50 minutes, the mixtureis concentrated and purified by silica gel chromatography (eluting withdichloromethane) to give diester (2) (1.81 g). Yield: 61%.

NMR (CDCl₃) δ: 3.18, 3.58 (2×d, J=8 Hz, 2H), 5.12, 5.24 (2×s, 2H), 6.93(s, 1H) ppm.

(2) To a solution of diester (2) (1.79 g) in dichloromethane (40 ml) areadded anisole (4 ml) and trifluoroacetic acid (4 ml) at 0° C. After 2.5hours' stirring, the mixture is concentrated and triturated in hexane togive monoester (3) (0.84 g). Yield: 73%. This is a mixture of cis andtrans (17.83) geometric isomers.

IR (CHCl₃) ν: 1730, 1690 cm⁻¹.

Preparation A-17 2-(2-Thienyl)-4-benzyloxycarbonyl-2-butenoic acid (2)##STR25##

Diester (1) (3.3 g) prepared in a manner similar to Preparation A-16 isdissolved in dichloromethane (60 ml), mixed with anisole (7 ml) andtrifluoroacetic acid (7 ml) at 0° C., stirred for 2.5 hours,concentrated, and triturated in hexane. Resulting solid is purified byhexane-ether giving monoester (2) (1.19 g). Yield: 56%.

Diester (1): IR (CHCl₃) ν: 1730sh, 1722, 1165 cm⁻¹.

Monoester (2): IR (CHCl₃) ν: 1730, 1695 cm⁻¹.

PREPARATION B (INTRODUCTION OF 3-SUBSTITUENTS) Preparation B-17beta-Amino-3-(2,2,2-trifluoroethylthio)-3-cephem-4-carboxylic acidp-nitrobenzyl ester (3) ##STR26##

(1) To a suspension of silver mercaptide (1) (1.86 g) inhexamethylphosphorotriamide (45 ml) is added sodium iodide 0.96 g).After stirring at room temperature for 50 minutes under nitrogen, themixture is mixed with trifluoromethanesulfonic acid trifluoroethyl ester(2.95 g). After stirring at room temperature for 1 hour, the reactionmixture is poured into ice water and extracted with ethyl acetate. Theextract is washed with water, dried, and concentrated. The residue ispurified by silica gel chromatography (eluting with benzeneethyl acetate(2:1) mixture) to give sulfide (2) (1.03 g). mp. 159°-160° C.

(2) To an ice cold solution of sulfide (2) (690 mg) in dichloromethane(22 ml) are added phosphorus pentachloride (675 mg) and pyridine (0.288ml). After stirring at room temperature for 2 hours, the mixture iscooled to -40° C., diluted with methanol (22 ml), stirred at 0° C. for 2hours, mixed with water (0.5 ml), and concentrated. The residue istriturated in ether to separate solid, which is suspended indichloromethane, washed with aqueous sodium hydrogen carbonate andwater, and concentrated to give amine (3) (562 mg).

IR (CHCl₃) ν: 3300br, 1775, 1735 cm⁻¹.

Preparation B-2 7beta-Amino-3-(2-fluoroethylthio)-3-cephem-4-carboxylicacid p-nitrobenzyl ester (4) ##STR27##

(1) To a suspension of silver mercaptide (1) (2 g) inhexamethylphosphorotriamide (60 ml) are added p-toluenesulfonic acid2-fluoroethyl ester (2.95 g) and sodium iodide (2.02 g). After keepingat room temperature for 4.5 hours, the mixture is poured into ice water(100 ml) and extracted with ethyl acetate. The extract is washed withwater, dried, concentrated, dissolved in dichloromethane, and dilutedwith ether to separate thioether (2). mp. 144°-149° C.

Yield: 87.8%.

IR (CHCl₃) ν: 3400, 1780, 1720, 1680, 1630 cm⁻¹.

(2) To a solution of thioether (2) (1.54 g) in dichloromethane (38.5 ml)are added pyridine (0.52 ml) and phosphorus pentachloride (1.207 g).After keeping at room temperature for 2.5 hours, the reaction mixture iscooled at -40° C., diluted with isobutanol (38.5 ml), kept at 0° C. for3 hours, and filtered to collect separated crystals of aminehydrochloride (3 ). Yield: 91%

IR (Nujol) ν: 3140, 2645, 2585, 1773, 1604, 1600, 1512, 1492, 1460 cm⁻¹.

(3) A mixture os amine hydrochloride (3) (1.186 g), ethyl acetate (50ml), sodium hydrogen carbonate (1.107 g), and water (30 ml) is stirredat 0° C. The organic layer is washed with aqueous sodium hydrogencarbonate and water, dried, and concentrated to give amine (4). Yield:94.2%.

IR (CHCl₃) ν: 3400, 1772, 1726, 1602, 1513 cm ⁻¹.

Preparation B-3 7beta-Amino-3-vinylthio-3-cephem-4-carboxylic acidp-nitrobenzyl ester (4) ##STR28##

(1) To a solution of 3-enol (1) (9.38 g) in acetonitrile (120 ml) areadded diphenyl chlorophosphinate (6.57 g) and diisopropylaminoethane(2.97 g). After stirring for 2 hours, this is mixed with2-(benzenesulfinyl)ethanethiol (3.16 g), diisopropylaminoethane (2.19g), and acetonitrile (6 ml), and stirred at -40° C. to -25° C. for 2.5hours. The mixture is poured into iced hydrochloric acid and extractedwith dichloromethane. The extract is washed with water, dried, andconcentrated. The residue is crystallized from ethyl acetate-ether togive sulfoxide (2) (6.84 g). mp. 174°-176° C.

(2) A solution of sulfoxide (2) (2 g) in 1,1,2-trichloroethane (40 ml)is refluxed for 11 hours under nitrogen. The reaction mixture isconcentrated, and crystallized from ether to give vinyl thioether (3)(1.38 g). mp. 193°-194° C.

(3) To a stirred and ice cold solution of vinyl thioether (3) (440 mg)in dichloromethane (15 ml) are added phosphorus pentachloride (358 mg)and pyridine (149 mg) under nitrogen. After stirring at room temperaturefor 2 hours, the reaction mixture is cooled to -40° C., diluted withmethanol (15 ml), and stirred for 2 hours at 0° C. The mixture is mixedwith water (1 ml), concentrated, washed with ether, suspended indichloromethane, and washed with aqueous 10% sodium hydrogen carbonateand water, dried, and concentrated. The residue is crystallized from amixture of dichloromethane and ether to give amine (4) (204 mg). mp.152°-154° C.

Preparation B-47beta-[2-(2-Aminothiazol-4-yl)-4-carboxy-2-butenamide]-3-cyanomethylthiomethyl-3-cephem-4-carboxylicacid (5) ##STR29##

(1) To a solution of bromomethyl compound (2) (340 mg) (prepared byamidating Amine (1) in a manner similar to Example 2) inN,N-dimethylformamide (3 ml) is added at -70° C. an ethanol solution ofsodium cyanomethylmercaptide (prepared from cyanomethyl thiolacetate (71mg) and sodium ethylate in ethanol). Afer 2 hours' stirring at -65° C.to -70° C., the mixture is poured into ethyl acetate, washed with water,dried and concentrated. The residue is purified by silica gelchromatography (eluting with a mixture of benzene and ethyl acetate(3:1) to give oxide (3). Yield: 57.2%.

(2) To a solution of oxide (3) (690 mg) in acetone (10 ml) are addedpotassium iodide (883 mg) and acetyl chloride (0.339 ml) at -35° C.After 90 minutes' stirring at -20° C. to -25° C., the mixture is dilutedwith ethyl acetate, washed with diluted sodium thiosulfate, and aqueoussodium hydrogen carbonate, dried, and concentrated to give sulfide (4).Yield: 85.6%.

(3) To a solution of sulfide (4) (550 mg) in anisole (10 ml) is added asolution of aluminium chloride (1.24 g) in anisole (5 ml) at -30° C.After 3 hours' stirring, the mixture is diluted with hydrochloric acidand washed with ethyl acetate. The aqueous layer is purified withsynthetic adsorbent HP 20 (Mitsubishi Chemical K.K.) and eluted to giveaminocarboxylic acid (5).

Yield: 74.4%.

Preparation B-57beta-Amino-3-(3,3,3-trifluoro-1-propenyl)-3-cephem-4-carboxylic aciddiphenylmethyl ester (3) ##STR30##

(1) Trifluoroacetaldehyde ethyl hemi ketal (4ml) is added dropwise tophosphoric acid heating at 165° C. Evolving trifluoroacetaldehyde iscondensed at -78° C. and dissolved in ethyl acetate (6 ml).

(2) To a suspension of phosphorane (1) (1.38 g) in a mixture (60 ml) ofdichloromethane and ethyl acetate (5:1) cooled at -70° C. is added thesolution prepared as in above (1). After stirring at -70° C. for 10minutes and 30 minutes at room temperature, the mixture is concentrated.The residue is purified by silica gel chromatography (eluting with amixture (9:1) of benzene and ethyl acetate) to give trifluoropropene(2). Yield: 91%.

IR (CHCl₃) ν: 3380, 1787, 1722, 1682 cm⁻¹.

(3) To a solution of trifluoropropene (2 ) (292 mg) in benzene (5 ml)are added pyridine (89 microliter) and phosphorus pentachoride (208 mg).After 2 hours' stirring at room temperature, the mixture is diluted withmethanol (5 ml). After 15 minutes' stirring, the reaction mixture isdiluted with ice-water, neutralized, and extracted with ethyl acetate.The extract is washed with water, dried, and concentrated to give amine(3). Yield: 65%.

Preparation B-6 7beta-Amino-3-difluoromethylthio-3-cephem-4-carboxylicacid diphenylmethyl ester (7) ##STR31##

(1) To a suspension of glycolate (1) (22.8 g) in dichloromethane (300ml) are added pyridine (4.63 ml) and thionyl chloride (4 ml) at -20° C.to -23° C. over a 24 minutes period. After stirring for 10 minutes at-20° C. and for 30 minutes at 0° C., the reaction mixture is washed withice water and dried over magnesium sulfate. To the solution are addedpyridine (4.63 ml) and triphenylphosphine (13 g). After stirring at roomtemperature for 2 hours and refluxing for 2 hours, the mixture is washedwith water, and purified by silica gel chromatography (eluting withbenzene-ethyl acetate (2:1) mixture) to give phosphoranilidene ester (2)(20.13 g).

(2) To a solution of phosphoranilidene ester (2) (16.65 g) in dioxane(80 ml) are added a solution of 99% silver perchlorate monohydrate (5.87g) in water (19 ml) and aqueous 60% perchloric acid (7.96 ml) at roomtemperature. After stirring for 1 hour, the mixture is diluted withdichloromethane and iced water. The organic layer is taken, washed withwater, dried, and concentrated to give silver mercaptide (3).

(3) To a solution of silver mercaptide (3) inhexamethylphosphorotriamide (100 ml) are added1-(difluoromethylthio)-3-chloroacetone (4) (3.95 g) and sodium iodide(3.55 g). After 2 hour stirring at room temperature, the reactionmixture is diluted with ethyl acetate and water. The organic layer istaken, washed with water, dried, and evaporated. The residue is purifiedby silica gel chromatography (eluting with benzene-ethyl acetate (1:1)mixture) to give ketone (5).

Above 1-(difluoromethylthio)-3-chloroacetone (4) can be prepared asfollows:

    CHF.sub.2 SCH.sub.2 COCl→CHF.sub.2 SCH.sub.2 COCH.sub.2 Cl(4)

To a solution of diazomethane in ether (200 ml) prepared fromN-nitrosomethylurea (20.6 g) is added dropwise a solution ofdifluoromethylthioacetyl chloride (10 g) in ether (20 ml) under icecooling over 20 minutes period. After stirring at 0° C. for 20 minutesand at room temperature for 2 hours, the mixture is saturated withhydrogen chloride under ice cooling over 30 minutes. The reactionmixture is diluted with ice water, ether layer is taken, washed withwater, dried, concentrated, and distilled to give (4) from fractionsevaporating at bp (1 mmHg) 52°-53° C. as colorless liquid.

(4) To a solution of ketone (5) (8.388 g) in toluene (200 ml) is addedhydroquinone (180 mg) and refluxed for 14 hours. After evaporatingtoluene, the mixture is purified by silica gel chromatography (elutingwith benzene-ethyl acetate (2:1) mixture) to give cephem (6) (4.42 g).

NMR (CDCl₃) δ: 3.58 (s, 2H), 3.73 (s, 2H).

(5) To an ice cold solution of cephem (6) (4.42 g) in dichloromethane(80 ml) are added pyridine (1.35 ml) and phosphorus pentachloride (3.17g). After stirring at 0° C. for 10 minutes and at room temperature for90 minutes, the mixture is cooled at -45° C. to -55° C., mixed with coldmethanol (110 ml), stirred at 0° C. for 30 minutes, diluted with icewater, and neutralized. The organic layer is taken, washed with water,dried, and concentrated. The residue is purified by silica gelchromatography (eluting with benzene-ethyl acetate (2:1) mixture to giveamine (7) (2.686 g).

NMR (CDCl₃) δ: 1.73 (brs, 2H) ppm.

    TABLE 1      Esters      ##STR32##        cis:     IR(CHCl.sub.3) ν:   No trans R.sup.0 R.sup.3 R.sup.5     R.sup.6 cm.sup.-1 NMR(CDCl.sub.3) δ: ppm Example No.       1  H Me H H nd 3.70˜4.30(m, 4H), 4.13, 4.16(2×s, 3H),     5.56, 5.62(2×d, J=5Hz, 1H), 6.20, (3-1)        6.26(2×d,     J=5Hz, 1H), 6.66˜6.83(m, 1H), 6.90, 7.26(2×t, J=9Hz, 1H),         7.06, 7.13(2×s, 1H) [D.sub.2 O]. 2 cis H Me H BH 1787, 1731,     1680, 3.35˜3.47(m, 2H), 3.58(d, J=8Hz, 2H), 3.70(s, 3H), 4.98(d,     J=5Hz, 1H), (4-4)       1280. 5.44(brs, 2H), 5.95, 6.04(dd, J.sub.1     =5Hz, J.sub.2 =9Hz, 1H), 6.47(s, 1H), 6.61(t,        J=8Hz, 1H),     6.56˜6.66(m, 1H), 6.95(s, 1H), 7.24˜7.48(m), 8.56(d, J=9Hz,           1H). 3 trans H Me H BH 1785, 1730, 1678, 3.40(d, J=8Hz, 2H),     3.35˜3.47(m, 2H), 3.68(s, 3H), 4.92(d, J-5Hz, 1H), (4-4)     1280. 5.59(brs, 2H), 5.94, 6.03(dd, J.sub.1 =5Hz, J.sub.2 =9Hz, 1H),     6.48(s, 1H), 6.53˜        6.63(m, 1H), 6.90(s, 1H), 7.14(t, J=8Hz,     1H), 7.23˜7.45(m, 10H), 8.65(d,        J=9Hz, 1H). 4 cis H Bzl H H     3270, 1770, 1735, 3.44(d, J=7.5Hz, 2H), 3.54˜3.67(m, 2H), 5.10(d,     J=5Hz, 1H), 5.17(s, 2H), (3-1)     CF.sub.3 COOH salt  1722 [Nujol].     5.80, 5.89(dd, J.sub.1 =5Hz, J.sub.2      =8Hz, 1H), 6.40(s, 1H), 6.42˜6.59(m, 2H), 7.41        (s, 5H),     9.39(d, J=8Hz, 1H) [CD.sub. 3 SOCD.sub.3 ]. 5 trans H Bzl H H 3280,     1772, 1735, 3.54˜3.69(m, 4H), 5.15(d, J=5Hz, 1H), 5.15(s, 2H),     5.78, 5.88(dd, J.sub.1 =5 (3-1)     CF.sub.3 COOH salt  1725 [Nujol].     Hz, J.sub.2 =8Hz, 1H), 6.45˜6.53(m, 1H), 6.66(s, 1H), 6.78(t,     J=7.5Hz, 1H),        7.40(s, 5H), 9.25(d, J=8Hz, 1H) [CD.sub.3      SOCD.sub.3 ]. 6 cis H Bzl H BH 1782, 1722, 1670, 3.32˜3.46(m,     2H), 3.62(d, J=8Hz, 2H), 4.95(d, J=5Hz, 1H), 5.13(s, 2H), (4-3)     1278. 5.31(brs, 2H), 5.92, 6.02(dd, J.sub.1 =5Hz, J.sub.2 =8Hz, 1H),     6.46(s, 1H), 6.53˜        6.61(m, 1H), 6.63(t, J=8Hz, 1H), 6.94(s,     1H), 7.21˜7.47(m), 8.67(d, J=        8Hz, 1H). 7 trans H Bzl H BH     1780, 1721, 1670, 3.30˜3.45(m, 4H), 4.88(d, J=5Hz, 1H), 5.11(s,2H),      5.52(brs, 2H), 5.92, (4-3)       1280. 6.02(dd, J.sub.1 =5Hz, J.sub.2     =8Hz, 1H), 6.41(s, 1H), 6.50˜6.65(m, 1H), 6.88(s,        1H),     7.15(t, J=7.5Hz, 1H), 7.16˜7.48(m), 8.61(d, J=8Hz, 1H). 8 cis Cbz     H H BH 1782, 1725, 1675, 3.56(d, J=8Hz, 2H), 3.4˜3.8(m, 2H),     5.04(d, J=5Hz, 1H), 5.26(s, 2H), (3-9)       1555 [Nujol]. 5.90(d,     J=5Hz, 1H), 6.70(t, J=8Hz, 1H), 6.60˜6.75(m, 1H), 6.95(s, 1H),        6.95(s, 1H), 7.25˜7.55(m, 15H) [CDCl.sub.3CD.sub.3 OD]. 9 trans     Cbz t-Bu H BH 3330, 1775, 1725, 1.34(s, 9H), 2.58˜3.26(m, 4H),     4.70(d, J=5Hz, 1H), 5.07, 5.51(ABq, J=13H (2-1),(15)       1670, 1630.     z, 2H), 5.68, 5.76(dd, J=5Hz, J=8Hz, 1H), 6.30˜6.39(m, 1H),     6.61(s, (5-1),       mp. 162˜164° C. 1H), 6.75(s, 1H),     7.10˜7.57(m, 15H), 7.67(d, J=8Hz, 1H). (6-1), (3).  10 15:85 Cbz      ##STR33##      H BH 3359, 1779, 1732,1675, 1281, 1091. nd (2-17)      11 1:1 Cbz     ##STR34##      H BH 3358, 1779, 1730,1675, 1283, 1092,mp. 150˜151° C.     1.06(d, J=7Hz, 1.5H), 1.18(d, J=7Hz, 1.5H), 2.63˜3.32(m, 4H),     4.66(d, J=4.5Hz, 1H), 4.85˜5.76(m, 6H), 6.31(m, 1H), 6.56(s, 1H),     6.68(s, 1/2H),6.71(s, 1/2H). (2-18)      12  Cbz     ##STR35##      H BH 3345, 1780, 1735,1679, 1287, 1092. nd (2-21)      13 2:3 Cbz     ##STR36##      H BH 3358, 1780, 1729,1676, 1282, 1240,1092.mp. 138˜140°     C. 1.58(d, J=6Hz, 9/5H), 1.64(d, J=6Hz, 6/5H), 2.65˜3.36(m, 4H),     4.38(d, J=6Hz, 2H), 4.69(d, J=5Hz, 1H), 5.06, 5.53(ABq, J=12Hz, 2H),     5.40˜5.79(m,3H), 6.28˜6.39(m, 1H). (2-18)  14 trans Cbz      ##STR37##      H BH 3455, 1779, 1728,1676, 1282, 1240,1093.mp. 133˜135°     C. 1.55(s, 3H), 1.61(s, 3H), 2.62˜3.32(m, 4H), 4.52(d, J=8Hz, 2H),     4.64(d,J=4.5Hz, 1H), 5.18(m, 1H), 5.02, 5.50(ABq, J=12Hz, 2H), 5.67(dd,     J=4.5Hz, 8Hz, 1H), 6.29(m, 1H), 6.58(s, 1H), 6.68(s, 1H).  15 trans Cbz      ##STR38##      H BH 3345, 1780, 1735,1675, 1635.mp. 132˜135° C. 1.56(s,     3H), 1.62(s, 3H), 2.64˜3.30(m, 4H), 4.45(brd, J=8Hz, 2H), 4.67(d,     J=5Hz, 1H), 5.16(brt, J=8Hz, 1H), 5.03, 5.50(ABq, J=12Hz, 2H), 5.65,5.74(     dd, J=5Hz, J=8Hz, 1H), 6.27˜6.36(m, 1H), 6.58(s, 1H), 6.69(s,1H),     7.13˜7.43(m, 16H), 7.60(d, J=8Hz, 1H). (2-20 )  16 mixt. Cbz      ##STR39##      H BH 3340, 1778, 1730,1677, 1283, 1088. nd (2-17)  17 1:4 Cbz Bzl H H     nd 3.00˜3.90(m,4H), 4.96, 5.00(2×d,J=5Hz,1H), 5.13(s,2H),     5.23(s,2H), 5.73˜ (2-7),(14)        5.88(m,1H), 5.76, 5.86(dd,J.sub     .1 =5Hz, J.sub.2 =9Hz,1H), 6.50˜6.60(m,1H), 6.93(s, (3-1).     1H). 7.11(t,J=8Hz,1H), 7.33(s,5H), 7.36(s,5H) [CDCl.sub.3CD.sub.3 OD].     18  Cbz Bzl H H 3160, 1775, 1720, 3.34˜3.50(m, 4H), 4.95(d, J=5Hz,     1H), 5.13(s, 2H), 5.23(s, 2H), 5.80(d, (2-7),(14)       1670, 1630.     J=5Hz, 1H), 6.48˜6.60(m,1H), 6.94(s, 1H), 7.03˜7.40(m, 11H).     (3-1). 19 1:4 Cbz Bzl H BH 3340, 1775, 1725, 3.04(s, 2H), 3.6˜4.1(m     , 2H), 4.58(d, J=5Hz, 1H), 4.8˜5.6(m, 4H), 5.68 (2-1),(15)     1670. (d, J=5Hz, 1H), 6.25(m, 1H), 6.59, 6.67(2×s, 1H), 6.63(s,     1H), 7.0˜7.9 (21),        (m, 22H). (6-1). 20 trans Cbz Bzl H BH     3830, 1780, 1725, 2.68˜3.36(m, 4H), 4.69(d, J=5Hz, 1H), 4.98(s,     2H), 5.03, 5.46(ABq, J=12H (2-5),(21)       1675, 1630. z, 2H), 5.65,     5.74(dd, J =5Hz, J =8Hz, 1H), 6.29˜6.40(m, 1H), 6.60(s, 1H (6-2),          mp. 131˜133° C. ), 6.64(s, 1H), 7.10˜7.47(m,     15H), 7.63(d, J=8Hz, 1H). 7. 21  Cbz MeBzl H BH 3340, 1775, 1725,     2.30(s, 3H), 2.70˜3.37(m, 4H), 4.71(d, J=5Hz, 1H), 4.95(d, 2H),     5.04, (2-7)       1670, 1630, 1560. 5.49(ABq, J=12Hz, 2H), 5.67,     5.76(dd, J.sub.1 =5Hz, J.sub.2 =8Hz, 1H), 6.30˜6.40(m,        1H),     6.62(s, 1H), 6.69(s, 1H), 7.05˜7.47(m, 20H), 7.66(d, J=8Hz, 1H).     22  Cbz PMB H BH 3325, 1770, 1720, 2.60˜3.65(m, 4H), 3.74(s, 3H),     4.67, 4.75(2×d, J=5Hz, 1H), 4.86˜5.53(m, (2-15),       1665,     1625, 1605, 4H), 5.65, 5.73; 5.73, 5.82(2×dd, J.sub.1 =5Hz,J.sub.2     =7Hz, 1H), 6.25˜6.50(m, 1H), (18).       1505, 1400. 6.59˜6.9     5(m, 4.5H), 7.05˜7.50(m, 18.5H), 7.65, 7.90(2×d, J=7Hz, 1H).     23 trans BOC Bzl H BH 3400, 3330, 1773, 1.50(s, 9H), 3.16(d, J=4.5Hz,     2H), 3.29(d, J=8Hz, 2H), 4.73(d, J=5Hz, (2-23)       1720, 1668, 1278,     1H), 5.04(s, 2H), 5.68, 5.77(dd, J.sub.1 =5Hz, J.sub.2 =7.5Hz, 1H),     6.35(t, J=4.5Hz,       1152. 1H), 6.64(s, 1H), 6.71(s, 1H), 7.17˜7.     48(m), 7.79(d, J=7.5Hz, 1H). 24 cis BOC Bzl H BH 3410, 3340, 1780,     1.53(s, 9H), 3.15˜3.37(m, 2H), 3.86(d, J=7Hz, 2H), 4.85(d, J=5Hz,     1H), (2-23)       1725, 1675, 1282, 5.17(s, 2H), 5.82, 5.91(dd, J.sub.1     =5Hz, J.sub.2 =8Hz, 1H), 6.43˜6.54(m, 1H), 6.70       1154. (t,     J=7Hz, 1H), 6.79(s, 1H), 6.83(s, 1H), 7.15˜7.49(m), 8.14(d, 1H).     25  HCO H H H nd 5.02(d, J=5Hz, 1H), 5.86(d, J=5Hz, 1H), 6.54˜6.64(     m, 1H), 7.04(t, J=8Hz, (3-1),(2),        1H), 7.16(s, 1H), 8.51(s, 1H)     [CDCl.sub.3CD.sub.3 OD]. (3). 26 trans HCO t-Bu H BH 3420, 1770, 1715,     1.39(s, 9H), 3.12(brd, 2H), 3.27(d, J=7Hz, 2H), 4.67(d, J=5Hz, 1H),     (2-18)       1665, 1625. 5.74, 5.83(dd, J.sub.1 =5Hz, J.sub.2 =8Hz, 1H),     6.29˜6.38(m, 1H), 6.62(s, 1H), 6.83        (s, 1H), 7.20˜7.47     (m, 11H), 7.68(d, J=8Hz, 1H), 8.51(s, 1H). 27 1:2 HCO BH H BH 1775,     1772, 1672, 3.60˜3.16(m, 2H), 3.46, 3.87(2×d, J=8Hz, 2H),     4.65, 4.70(2×d, J=5Hz, (5-1)       1280, 1152. 1H), 5.72, 5.81;     5.77, 5.86(2×dd, J.sub.1 =5Hz, J.sub.2      =8Hz, 1H), 6.26˜6.45(m,1H),        6.61, 6.76(2×s, 1H),     6.66(s, 1H), 6.87, 6.95(2×s, 1H), 7.10˜7.47(m),        7.64,     7.86(2×d, J=2Hz, 1H), 8.40, 8.43(2×s, 1H), 11.27, 11.51(2.tim     es.brs,        1H).      28 1:2     ##STR40##      H H H 1761, 1720, 1700[Nujol] 4.61, 4.75(2×s, 2H), 5.45, 5.51(2.ti     mes.d, J=5Hz, 1H), 6.08, 6.19(2×dd, J.sub.1 =5Hz, J.sub.2 =8Hz,     1H), 7.01, 7.30(2×t, J=8Hz, 1H), 7.60, 7.72(2×s, 1H),     8.268.74(2×d, J=8Hz, 1H) [CD.sub.3 SOCD.sub.3 ]. (3-2)  29      ##STR41##      Bzl H H 3150, 1770, 1718,1680, 1278, 1152[Nujol]. 3.38˜3.70(m,     4H), 4.38(s, 2H), 5.06(d, H=5Hz, 1H), 5.13(s, 2H), 5.73,5.82(dd, J.sub.1     =5Hz, J.sub.2 =8Hz, 1H), 6.41˜6.52(m,1H), 6.62(t, J=7.5Hz,     1H),7.24(s, 1H), 7.38(s, 5H), 9.00(d, J=8Hz, 1H), 12.57(brs, 1H)     [CD.sub.3 SOCD.sub.3 ]      30 5:6     ##STR42##      Bzl H BH 3320, 1780, 1732,1727, 1680. 3.13, 3.26(m, 2H), 3.36, 3.76(2.ti     mes.d, J= 8Hz, 2H), 3.87, 4.69; 4.16, 4.32(2×ABq. J=17Hz, 2H),     4.70, 4.79(2×d, J=5.0Hz, 1H), 5.06, 5.17(2×s, 2H),5.69,     5.78; 5.78, 5.87(2×dd, J.sub.1 =5.0Hz, J.sub.2 =9.0Hz, 1H),     6.31˜6.48(m, 1H),6.66, 6.75(2×s, 1H), 6.72, 6.83(2×s,     1H), 6.67(t, 8Hz, 5H/11), 7.18˜7.49(m), 7.73, 7.94(2×d,     J=9Hz, 1H). (2-18)      31 trans     ##STR43##      Bzl H BH 3400, 1785, 1725,1670, 1630. 0.28(s, 6H), 0.93(s, 9H),     3.18˜3.78(m, 2H), 3.47(d, J=7.5Hz, 2H), 4.79(s, 1H), 4.98(d,     H=5Hz, 1H), 5.16(s, 2H), 6.00, (dd, J.sub.1 =5Hz, J.sub.2 =9Hz,1H),     6.48(s, 1H), 6.57˜6.67(m, 1H), 6.98(s, 1H), 7.17(t, J=7.5Hz, 1H),  .     72˜7.6(m, 15H), 8.65(d, J=9Hz, 1H). (2-1)      32 cis     ##STR44##      Bzl H BH 3390, 1780, 1720,1670, 1630. 0.28(s, 6H), 0.94(s, 9H),     3.17˜3.75(m, 2H), 3.66(d, J=5Hz, 2H), 4.68(s, 1H), 4.99(d, J=5Hz,     1H), 5.16(s, 2H), 6.00(dd, J.sub.1 =5Hz, J.sub.2 =9Hz, 1H),6.50(s, 1H),     6.57˜6.65(m, 1H), 6.68(t, J=7.5Hz, 1H), 6.97(s,1H), 7.1˜7.6(m     , 15H), 8.35(d, J=9Hz, 1H). (2-1)  33 1:3 Cbz Bzl Me BH 3320, 1765,     1725, 2.00(s, 3H), 2.27, 2.77(ABq, J=17Hz, 2H), 3.03, (AB part of ABX,     J=16Hz, (2-5)       1675. 3/2H), 3.63(AB part. of ABX, J=16Hz, 1/2H),     4.77(d, J=4Hz, 1H), 4.9˜5.6        (m, 5H), 6.61, 6.66(2×s,     1H), 6.69, 6.75(2×s, 1H), 6.9˜7.5(m, 21H), 7.70     7.89(2×d, J=7Hz, 1H). 34 1:2 Cbz Bzl CHCH.sub.2 BH 3330, 1770,     1725, 2.70˜3.94(m, 4H), 4.73, 4.79(2×d, J=4Hz, 1H), 4.90.abou     t.5.30(m, 7H), 6.56˜ (2-15)       1675, 1620. 6.64(m,2H), 6.90.abou     t.7.50(m, 22H), 7.74, 7.92(2×d, J=7Hz, 1H). 35 2:1 Cbz Bzl     CHCHCN(Z) BH 3407, 3345, 2210, 2.7˜4.2(m, 4H), 4.85, 4.92(2×d     , J=4.5Hz, 1H), 5.07(s, 2H), 5.13(s, 2H), (2-3)       1783, 1728, 1679,     5.20, 5.39(2×d, J=12Hz, 1H), 5.70(m, 1H), 6.49, 6.76(2×s,     1H), 6.63,       1631. 6.67(2×s, 1H), 6.5˜8.1(m, 23H). 36     2:1 Cbz Bzl CH=CHCN(Z) H 3168, 2193, 1785, 3.50(m, 2H), 4.02(m, 2H),     5.13(d, J=4.5Hz, 1H), 5.17(s, 2H), 5.28(s, (3-1)       1726, 1672 2H),     5.45(d, J=12.5Hz, 1H), 5.90(d, J=4.5Hz, 1H), 6.95, 7.07(2×m, 1H),          [Nujol]. 6.98(s, 1H), 7.1˜7.7(m, 11H) [CDCl.sub.3CD.sub.3     OD]. 37  Cbz Bzl CHCHCOOt-Bu (E) BH 3391, 1779, 1728, 1.41(s, 9H),     2.3˜4.2(m, 4H), 5.04, 5.08(2×d, J=4.5Hz, 1H), 5.10(s, 2H),     (2-7)       1618. 5.17(s, 2H), 5.67(2×m, 1H), 5.94(d, J=16Hz, 1H),     6.63, 6.89(2×s, 1H).        6.72, 6.76(2×s, 1H), 6.4˜7.     7(m, 17H), 7.86(d, J=16Hz, 1H). 38  Cbz Bzl CHCHCOOt-Bu (E) H 3170,     1780, 1730, 1.49(s, 9H), 3.3˜4.2(m, 4H), 5.03, 5.07(2×d,     J=4.5Hz, 1H), 5.14(s, 2H), (3-1)       1613, 1302, 1229 5.23(s, 2H),     5.82(2×m, 1H), 5.96(d, J=16Hz, 1H), 6.65(m, 0.5H), 6.91(s,     [Nujol]. 1H), 7.0˜7.5(m, 10.5H), 7.86(d, J=16Hz, 1H). 39  Cbz Bzl     CHCHCF.sub.3 (5E:2Z) BH 3330, 1775, 1725, 2.7˜3.6(m, 4H), 4.75.abou     t.4.95(m, 1H), 4.95˜6.0(m, 6H), 6.4˜6.8(m, 2H), 7.05˜     (2-16)       1675, 1620. 7.85(m, 23H). 40  Cbz Bzl CHCHCF.sub.3 (Z) BH     3325, 3390, 1775, 2.7˜3.8(m, 4H), 4.8˜5.9(m, 7H), 6.55˜     6.85(m, 3H), 7.07˜7.7(m, 22H). (2-16)       1725, 1672, 1625. 41     1:2 Cbz Bzl CH.sub.2 N.sup.⊕ C.sub.5 H.sub.5 Cl.sup.⊖ H nd     3.16, 3.68(ABq, J=18Hz, 2H), 3.51(d, J=8Hz, 2H), 5.12(s,2H), 5.28(s,2H),     (2.30)        5.20(d, J=5Hz, 1H), 5.82(d, J=5Hz, 1H), 5.37, 5.76(ABq,     J=20Hz, 2H),        7.0, 7.15(2×s, 1H), 7.35(s, 5H), 7.42(s, 5H),     6.8˜7.5(m, 1H), 8.0˜9.3        (m, 5H) [CD.sub.3 ODCD.sub.3     COCD.sub.3D.sub.2 O]. 42 cis Cbz Bzl CH.sub.2 OMe BH 3390, 1780, 1728,     3.16(s, 3H), 3.25(s, 2H), 3.54, 3.68(AB parts of ABX, J.sub.1 =19.2Hz,     J.sub.2 = (2-9)       1675, 1304, 1168, 7Hz, 2H), 4.14, 4.28(ABq,     J=15.5Hz, 2H), 4.91(d, J=4.5Hz, 1H), 5.12(s,       1092. 2H), 5.16,     5.34(ABq, J=18Hz, 2H), 5.65(dd, J.sub.1 =4.5Hz, J.sub.2 =8.5Hz, 1H),     6.62        (t, J=7Hz, 1H), 6.75(s, 1H), 6.79(s, 1H), 7.23˜7.40(m,     21H), 8.10(d, J=        8.5Hz, 1H). 43 trans Cbz Bzl CH.sub.2 OMe BH     3425, 1778, 1726, 2.95, 3.19(AB parts of ABX, J.sub.1 =17Hz, J.sub.2     =8.1Hz, 2H), 3.14(s, 3H), 3.18(s, (2-9)       1675, 1302, 1220, 2H),     4.09, 4.27(ABq, J=13.5Hz, 1H), 4.80(d, J=4.5Hz, 1H), 5.02(s, 2H),     1090. 5.09, 5.37(ABq, J=12.6Hz, 2H), 5.50(dd, J.sub.1 =4.5Hz, J.sub.2     =7Hz, 1H), 6.57(s,        1H), 6.63(s, 1H), 7.10(t, J=8.1Hz, 1H),     7.20˜7.42(m, 21H), 7.74(d, J=        7Hz, 1H). 44  Cbz Bzl     CH.sub.2 OCOMe BH 3400, 3330, 1775, 1.96(s, 3H), 2.82˜3.70(m, 4H),     4.56˜5.73(m,8H), 6.60˜6.77; 7.04˜7.50 (2-11)     1725, 1670, 1625. (2×m, 23H). 45 1:10 Cbz Bzl CH.sub.2 OCONH.sub.2     BH 3320, 1775, 1720, 3.49, 3.64(ABq, J=18Hz, 2H), 3.57(d, J=8Hz, 2H),     4.75, 4.97(ABq, J=12Hz, (2-1)       1710 [Nujol]. 2H), 5.15(s, 2H),     5.20(d, J=4Hz, 1H), 5.28(s, 2H), 5.75˜6.30(m, 3H),        6.93(s,     1H), 7.10(t, J=8Hz, 1H), 7.20(s, 1H), 7.2˜7.7(m, 20H) [CD.sub.3     COCD.sub.3 ] 46  Cbz Bzl CH.sub.2 SMe BH 1770, 1750, 1720, 1.82(s, 3H),     3.3˜3.7(m, 6H), 5.03(d, J=5Hz, 1H), 5.12(s, 2H), 5.25(s, (2-18)        1670. 2H). 5.6˜5.75(m, 1H), 6.89(s, 1H), 6.90(s, 1H), 6.66,     7.11(2×t, J=8Hz,        1H), 7.2˜7.5(m, 20H) [CDCl.sub.3CD.su     b.3 OD]. 47  Cbz Bzl CH.sub.2 SCH.sub.2      CN BH 3230, 2245, 1785, 2.7˜3.4(m, 6H), 3.57, 3.77(Abq, J=14Hz,     2H), 4.93(d, J=4Hz, 1H), 5.06(s, (6-4)       1730, 1680, 1620, 2H),     5.18, 5.27(2×s, 2H), 5.48(dd, J.sub.1 =4Hz, J.sub.2 =9Hz, 1H),     6.69(s, 1H),       1560. 6.76(s, 1H), 7.1˜7.5(m, 20H), 8.46(d,     J=9Hz, 1H). 48  Cbz Bzl CH.sub.2 SCHF.sub.2 BH 3400, 3330, 1775, 3.14(t,     J=9Hz, 2H), 4.87(d, J=5Hz, 1H), 5.05(s, 2H), 5.44 (dd, J.sub.1 =5Hz,     (2-27)       1735, 1725, 1675, J.sub.2 =8Hz, 2H), 6.60(t, J=56Hz, 1H),     6.15(s, 1H), 6.18(s, 1H), 7.10(t, J=       1630. 9Hz, 1H), 7.2˜7.4(     m, 20H), 7.74(d, J=8Hz, 1H)      49 2:3 Cbz Bzl     ##STR45##      BH 3380, 3160br 1775,1723, 1675, 1220. 3.16˜4.20(m, 6H), 4.81.abou     t.5.26(m, 6H), 5.39˜6.19(m, 1H), 6.63˜6.85, 7.05˜7.36(m     , 24H), 7.47(s, 1H), 8.18, 8.48(2×d, J=8Hz, 1H). (2-7)  50 3:5     MeCbz MeBzl      ##STR46##      BH 1780, 1722, 1672. 2.30(s, 6H), 2.77˜3.27, 3.90˜3.60,     4.17˜4.57(3×m, 6H), 4.35(d, J=5Hz,1H), 4.90˜5.50(m,     5H), 6.60(s, 1H), 6.73(s, 1H), 7.00˜7.50(m, 13H), 8.37(s, 1H).     (2-10)      51 1:1 Cbz Bzl     ##STR47##      BH 3403, 3175, 1775,1721, 1670, 1621,1542. 3.36(d, J=8Hz, 2H), 3.59(brs,      2H), 4.36(Abq, J=14Hz, 2H), 4.98 5.01(2×d, J=4Hz, 1H), 5.10(s,     2H), 5.22(s, 2H), 5.68, 5.78(2×d, J=4Hz, 1H),6.87, 6.89, 6.91(3.tim     es.s, 2H), 7.1˜7.6(m, 21H), 8.93, 8.94(2×s, 1H) [CDCl.sub.3CD     .sub.3 OD(10:1)]. (2-8),(18)      52  Cbz Bzl     ##STR48##      BH 3385, 3160, 17731720, 1668, 1620,1541. 2.61(s, 3H), 3.36(d, J=8Hz,     2H), 3.54(brs, 2H), 4.30(ABq, J=14Hz, 2H),4.96, 5.00(2×d, J=4Hz,     1H), 5.11(s, 2H), 5.23(s, 2H), 5.68, 5.77(2×d, J=4Hz, 1H), 6.88(s,     2H), 7.00˜7.55(m, 22H) [CDCl.sub.3CD.sub.3 OD(10:1)]. (2-28),(18).      53 1:1 Cbz Bzl     ##STR49##      BH 3380, 3170, 1780,1725, 1675, 1603,1564. 3.47(d, J=8Hz, 2H), 3.52(brs,      2H), 4.09(brs, 2H), 4.97, 5.01(2×d, J=4Hz,1H), 5.11, 5.13(2×     s, 2H), 5.23(s, 2H), 5.72, 5.78(2×d, J=4Hz, 2H),6.86, 6.89,     6.90(3×s, 2H), 7.00˜7.60(m, 20H), 6.65, 7.12(2×t,     J=8Hz, 1H)[CDCl.sub.3CD.sub.3 OD(10:1)]. (2-25)      54 1:1 Cbz Bzl     ##STR50##      BH 3385, 3170, 1779,1723, 1673, 1620,1560. 3.38(d, J=8Hz, 2H), 3.51(brs,      2H), 4.06(brs, 2H), 4.23(brs, 2H), 4.98,5.01(2×d, J=4Hz, 1H),     5.11(s, 2H), 5.20(s, 2H), 5.78(d, J=4Hz, 1H), 6.87(s, 1H), 6.90(s, 1H),     7.00˜7.60(m, 22H) [CDCl.sub.3CD.sub.3 OD(10:1)]. (2-15)  55 cis     Cbz Bzl      ##STR51##      BH 3400, 1785, 1725,1670. 3.40(s, 2H), 3.61(d, J=Hz, 2H), 3.73(s, 3H),     4.11 4.43(ABq, J=14Hz, 2H)4.91(d, J=5Hz, 1H), 5.11(s, 2H), 5.14,     5.24(ABq, J=12Hz, 2H), 5.65(dd,J.sub.1 =8Hz, J.sub.2 =5Hz, 1H), 6.62(t,     J=7Hz, 1H), 6.78(s, 1H), 6.81(s,1H), 7.1˜7.6(m, 20H), 8.27(d,     J=8Hz, 1H). (2-29)      56 trans Cbz Bzl     ##STR52##      BH 1785, 1730, 1675. 2.98(d, J=8Hz, 2H), 3.23(s, 2H), 3.76(s, 3H),     3.98, 4.52(ABq, J=14Hz,2H), 4.80(d, J=5Hz, 1H), 5.06(s, 2H), 5.10(s,     2H), 5.40(dd, J.sub.1 =5Hz, J.sub.2 =6Hz, 1H), 6.52(s, 1H), 6.77(s, 1H),     7.08(t, J=8Hz 1H), 6.81 (s, 1H), 7.1˜7.6(m, 20H),7.77(d, J=6Hz,     1H). (2-29)  57  Cbz Bzl Ome BH 3325, 1760, 1715, 1.98 2.69(ABq, J=16Hz,     2H), 2.76˜4.01(m, 2H), 3.52(s, 3H), 4.92˜5.54(m, (2-15)      1670, 1625. 6H), 6.66(s, 1H), 6.88(s, 1H), 7.01˜7.50(m, 2H). 58     Cbz Bzl OSO.sub.2 Me BH 3340, 1785, 1735, 2.65˜3.75(m, 2H),     2.94(s, 3H), 3.51(brs, 2H), 4.86(d, J=5Hz, 1H), 5.03 (2-12)       1675,     1630. (s, 2H), 5.02, 5.49(ABq, J=13Hz, 2H), 5.61, 5.70(s, 2H), 5.02     5.49(ABq,        J=13Hz, 2H), 5.61, 5.70(dd, J.sub.1 =5Hz, J.sub.2 =8Hz,     1H), 6.50, 6.53 (6.60(3×s,        2H). 59 1:2 Cbz Bzl Cl BH 3350,     1785, 1740, 2.64˜3.95(m, 2H), 3.37(brs, 2H), 4.78, 4.80(2×d,     J=6Hz, 1H), 4.94˜5.13 (2-28)       1685, 1635. (m, 2H), 5.00,     5.10(2×s, 2H), 5.58(dd, J.sub.1 =8Hz, J.sub.2      =8Hz, 1H), 6.55˜6.67;        6.95˜7.50(2×m 23H). 60     BOC Bzl Cl PNB 1778, 1745, 1727, 1.52(s, 9H), 3.38(d, J=8Hz, 2H),     4.89(d, J=2Hz, 1H), 5.13(s, 2H), 5.28 (2-24) 2-Cephem isomer  1675,     1350, 1150, (d, J=4Hz, 1H), 5.31(s, 2H), 5.43, 5.51(dd, J.sub.1 =4Hz,     J.sub.2 =7Hz, 1H), 6.35(d,    J=2Hz, 1H), 6.93(s, 1H), 7.18(t, J=8Hz,     1H), 7.33(s, 5H), 7.52(d, J=8Hz,    2H), 8.20(d, J=7Hz, 1H), 8.23(d,     J=8Hz, 2H), 8.99(brs, 1H). 61  MeCbz MeBzl SCH.sub.2 CH.sub.2 F PNB     3340, 1780, 1732, 2.32(s, 6H), 2.7˜3.3(m, 4H), 3.39(s, 2H),     4.49(dt, J.sub.1 =47Hz, J.sub.2 =6Hz, 2H), (2-17)       1676, 1620,     1606, 4.82(d, J=4Hz, 1H), 5.02(s, 2H), 4.68, 5.48(ABq, J=19Hz, 2H),     5.21(s,        2H), 6.83(s, 1H), 7.0˜7.3(m, 9H), 7.46(d, J=9Hz,     1H), 7.67(d, 8Hz, 1H),        8.14(d, J=9Hz, 2H). 62  MeCbz MeBzl     SCH.sub.2 CH.sub.2 F BH 3345, 1757, 1730, 2.26(s, 6H), 2.1˜2.7(m,     2H), 2.7˜3.3(m, 4H), 4.31(dt, J.sub.1 =6Hz, J.sub.2 =46Hz, (2-5)         1672, 1630, 1557, 2H), 4.8˜4.5(m, 6H), 6.65(s, 1H), 6.80(s,     1H), 7.0˜7.7(m, 2H).       1528. 63 1:1 Cbz Bzl SCH.sub.2 CF.sub.3     PNB 3330, 1775, 1725, 2.8˜3.7(m, 6H), 4.75˜5.75(m, 8H),     6.82(s, 1H), 7.0˜7.7(m, 12H), 7.45, (2-22)       1665. 8.15(ABq,     J=9Hz, 4H). 64  Cbz Bzl SCH.sub.2 CF.sub.3 H 3170br 1775, 1725, nd (3-1)           1670. 65  Cbz Bzl SCHCH.sub.2 BH 3320, 1770, 1750, 2.5˜3.8(m     4H), 4.7˜5.8(m, 8H), 5.9˜8.0(m, 26H). (2-17)       1720,     1670. 66  Cbz Bzl SCHCH.sub.2 PNB 3325, 1775, 1720, 2.7˜3.8(m,     2H), 3.43(s, 2H), 4.75˜5.70(m, 10H), 6.25˜8.3(m, 19H),     (2-17)       1670.

    TABLE 1 (2)      Esters      ##STR53##        cis:       IR(CHCl.sub.3)ν:   No. trans R.sup.0 R.sup.1 R.sup.2     R.sup.3 R.sup.5 R.sup.8 cm.sup.-1 NMR(CDCl.sub.3)δ: ppm Example     No.  1 cis Cbz II -- Bzl Me BH 3400, 1765, 1720, 1.96(s, 3H), 2.60.     3.68(ABq. J=18Hz, 2H), 4.88(d, J=4.5Hz. 1H). (2-28)         1680.     5.07(s, 2H), 5.13, 5.27(ABq. J=12Hz, 2H), 5.88(dd, J.sub.1 =4.5Hz,     J.sub.2 =          7Hz, 1H), 6.59(s, 1H), 6.86(s, 1H), 7.01(s, 1H),     7.0˜ 7.6(m,          20H), 8.21(d, J=7Hz, 1H). 2 cis Cbz H 13  Bzl     CHCH.sub.2 BH 3400, 1770, 1725, 3.06 3.18(ABq, J=18Hz, 2H), 4.95(d,     J=5Hz, 1H), 4.9˜5.4(m, 6H), (2-23)         1685. 5.93(dd, J.sub.1     =5Hz, J.sub.2 =7.5Hz, 1H), 6.60(s, 1H), 6.89 (s, 1H), 7.00          (s,     1H), 6.85˜7.6(m, 21H), 8.21(d, J=7.5Hz, 1H), 10.09(brs, 1H). 3 cis     Cbz H -- Bzl CH.sub.2 OCOMe BH 1770, 1725, 1680. 1.98(s, 3H), 2.88,     3.28(ABq. J=19Hz, 2H), 4.52˜5.22(m, 7H), 5.93 (2-17)          (dd,     J.sub.1 =8Hz, 1H), 6.60(s, 1H), 6.88(s, 1H), 7.02(s, 1H),     7.0˜7.6(m, 20H), 8.00(d, J=8Hz, 1H). 4 trans Cbz H -- Bzl CH.sub.2     OCOMe BH 1780, 1735, 1675. 1.97(s, 3H), 3.18(brs, 1H), 4.85(d, J=5Hz,     1H), 4.52˜5.57(m, (2-17)          7H), 6.70(s, 1H), 6.98(s, 1H),     7.1˜7.6(m, 20H), 7.90(d, J=7.5Hz.          1H). 5 cis Cbz H     CH.sub.2 CH.sub.2 Bzl H BH 3350, 1770, 1720, 2.55(m, 4H), 3.30(m, 2H),     4.85(d, J=6.0Hz, 1H), 5.06(s, 4H), (2-20)         1660, 1620, 1520,     5.90(m, 1H), 6.40(m, 1H), 6.63(s, 1H), 6.81(s, 1H), 7.30(m, 21H),      1390, 1270. 6 trans Cbz H CH.sub.2 CH.sub.2 Bzl H BH 3350, 1770, 1720,     2.30(m, 4H), 3.08(m, 2H), 4.63(d, J=6.0Hz, 1H), 5.00(s, 4H), (2-20)        1660, 1620, 1520, 5.70(m, 1H), 6.29(m, 1H), 6.53(s, 1H), 6.56(s, 1H),     6.98(m, 1H),         1390, 1270. 7.30(m, 21H).      7  Cbz H     ##STR54##      Bzl H BH 3330, 1770, 17251670. 0.9˜1.5(2×d, 3H), 3.0˜3     .3(m, 2H), 3.4˜4.5(m, 1H). (2-21)      8 exo Cbz H     ##STR55##      Bzl H BH 3390, 1785, 17351690sh. 1.74, 1.79, 1.90 2.00(4×s, 3H),     3.1˜3.4(m, 2H) (2-21)  9 cis Cbz H (CH.sub.2).sub.2 Bzl H BH 3325,     2900, 1770, 1.75(m, 2H), 2.30(m, 4H), 3.25(m, 2H), 4.80(d, J=6.0Hz, 1H),     (2-21)         1720, 1660, 1620, 5.08(s, 4H), 5.75(m, 1H), 6.32(m, 1H),     6.61(s, 1H), 6.78(s, 1H),         1520, 1400, 1286. 6.90(m, 1H), 7.30(m,     21H). 10 trans Cbz H (CH.sub.2).sub.2 Bzl H BH 3325, 2910, 1770, 1.70(m,     4H), 2.22(m, 4H), 3.11(m, 2H), 4.65(d, J=6Hz, 1H), 5.02 (2-21)     1720, 1660, 1620, (s, 4H), 5.70(m, 1H), 6.30(m, 1H), 6.48(s, 1H),     6.60(s, 1H),         1530, 1400, 1280. 7.00(m, 1H), 7.30(m, 21H). 11 cis     BOC H >CMe.sub.2 Bzl H BH 3390, 1780, 1720, 1.52(s, 15H), 3.1˜3.7(m     , 2H), 4.91(d, J=5Hz, 1H), 5.13(s, 2H), (2-6)         1665. 5.87(dd,     J.sub.1 =5Hz, J.sub.2 =8Hz, 1H), 6.45(s, 1H), 6.54˜6.64(m, 1H),           6.82(s, 1H), 6.94(s, 1H), 7.1˜7.5(m, 15H).  12 trans BOC H      ##STR56##      Bzl H BH 3400, 3340, 1780,1720, 1665. 1.34(s, 3H), 1.36(s, 3H), 1.52(s,     9H), 3.09(d, J=4Hz, 2H), 4.50,4.78(ABq, J=12 Hz, 2H), 4.67(d, J=5Hz,     1H), 5.62(dd, J.sub.1 =5Hz, J.sub.2 =8Hz, 1H), 6.32(t, J=4Hz, 1H),     6.51(s, 1H), 6.61(s, 1H), 7.11(s,1H), 7.1˜7.5(m, 15H). (2-6)  13     3:2 Cbz Cl -- Bzl H BH 3400, 1780, 1720. nd (2-1) 14 1:1 Cbz Cl CH.sub.2     CH.sub.2 Bzl H BH 3390, 1785, 1715, 2.6˜3.0(m, 2H), 3.25(s, 3H),     3.0˜3.6(m, 4H), 3.55˜3.85(m, 2H), (2-16)   NMEM      1670     4.97, 5.02(d×d, J=4.5Hz, 1H), 5.09, 5.11(2×s, 2H), 5.33(s,     2H),          5.55 5.67(2×s, 2H), 5.8˜6.2(m, 1H), 6.55˜     6.75(m, 1H), 6.68.          7.03(2×s, 1H), 6.95(s, 1H), 7.15˜     7.6(m, 21H). 15  Cbz Cl (CH.sub.2).sub.3 Bzl H BH 1785, 1725. 1.70˜     2.90(m, 6H), 3.25˜3.50(m, 2H), 4.87(d, J=5Hz, 1H), 5.00(s, (2-21)             2H), 5.23(s, 2H), 5.95(dd, J.sub.1 =5Hz, J.sub.2 =9Hz, 1H),     6.53(t, J=4Hz,          1H), 6.71(s, 1H), 6.82(s, 1H), 7.0˜7.5(m,     20H). 16  Cbz Cl SCH.sub.2 Bzl H BH nd 3.23(brs, 2H), 3.60(s, 2H),     4.80(d, J=5Hz, 1H), 5.03(s, 2H), 5.07, (2-21)          5.50(ABq, J=12Hz,     2H), 5.83(dd, J.sub.1 =5Hz, J.sub.2 =9Hz, 1H), 6.35(t, J=          4Hz,     1H), 6.77(s, 1H), 6.90(s, 1H), 7.0˜7.6(m, 20H).

    TABLE 1 (3)      Esters      ##STR57##        cis:      IR(CHCl.sub.3) ν:  Example No trans X R.sup.1 R.sup.2     R.sup.4 R.sup.5 cm.sup.-1 NMR(CDCl.sub.3) δ: ppm No.       1 cis SO H CH.sub.2 H H 1795, 1725, 1670. 3.1˜4.12(m, 2H),     3.57(d, J=7Hz, 2H), 4.54(d, J=5Hz, 1H), 5.07(s, 2H), 5.18(s, (2-20)     α      2H), 5.61(dd, J.sub.1 =5Hz, J.sub.2      =7Hz, 1H), 6.3˜6.4(m, 1H), 6.60(t, J=7Hz, 1H), 6.85(s,     1H), 6.88(s, 1H), 7.1˜7.5(m, 20H), 8.53(d, J=7Hz, 1H). 2 trans SO     H CH.sub.2 H H nd 2.9˜4.15(m, 4H), 4.45(d, J=5Hz, 1H), 5.06(s,     2H), 5.10, 5.30(ABq, J=12Hz, 2H), (2-20)   α      5.47(dd, J.sub.1     =5Hz, J.sub.2 =7Hz, 1H), 6.2˜6.4(m, 1H), 6.77(s, 1H), 6.82(s, 1H),     7.11         (t, J=8Hz, 1H), 7.1˜7.5(m, 20H), 8.03(d, J=7Hz, 1H).     3 trans SO H CH.sub.2 H H 1800, 1720, 1670. 3.0˜3.9(m, 2H),     3.37(d, J=7Hz, 2H), 4.36(d, J=5Hz, 1H), 5.10(s, 2H), 5.18(s, (2-20)     β      2H), 6.16(dd, J.sub.1 =5Hz, J.sub.2      =9Hz, 1H), 6.3˜6.4(m, 1H), 6.84(s, 1H), 6.92(s, 1H),     7.1˜7.5(m, 21H), 9.50(brs, 1H), 9.56(d, J=9Hz, 1H). 4  SO H     CH.sub.2 H CH.sub.2 SCH.sub.2 CN 3200, 2245, 1800, 2.81(s, 2H), 3.34(d,     J=7Hz, 2H), 3.60(s, 2H), 3.24, 3.79(ABq, J=17Hz, 2H), (2-11)     1720, 1672, 1615, 4.52(d, J=5Hz, 1H), 5.08(s, 2H), 5.14(s, 2H), 6.15(dd,     J.sub.1 =5Hz, J.sub.2 =10Hz, 1H), B-4        1550. 6.78(s, 1H), 6.94(s,     1H), 7.1˜7.5(m, 20H), 9.54(d, J=10Hz, 1H), 9.67(brs, 1H).  5 1:1     SO H CH.sub.2 H      ##STR58##      1800, 1722, 1668. 2.29(s, 3H), 2.30(s, 3H), 3.27, 3.80(ABq, J=18Hz,     2H), 3.31, 3.40(2×d, J=8Hz,2H), 4.00(brs, 2H), 4.50(d, J=5Hz, 1H),     5.07, 5.11(2×s, 4H), 6.08, 6.19(dd,J.sub.1 =10Hz, J.sub.2 =5Hz,     1H), 6.81(s, 1H), 6.83(s, 1H), 6.97˜7.43(m, 19H), 8.33(s,1H),     9.43(brs, 1H), 9.71(d, J=10Hz, 1H). (2-11)  6  SO H CH.sub.2 H OH 1800,     1730, 1640, 3.30˜3.80(m, 4H), 4.66(d, J=5Hz, 1H), 5.14(s, 2H),     5.23(s, 2H), 5.93(d, J=5Hz, (2-10)   β     1615. 1H), 6.84(s, 1H),     6.88(s, 1H), 7.10˜7.70(m) [CDCl.sub.3CD.sub.3 OD]. 7 1:1 O H     CH.sub.2 OMe CHCH.sub.2 3380, 3150, 1765, 2.80˜3.90(m, 2H), 3.30,     3.47(2×s, 3H), 4.0˜5.5(m, 9H), 6.4˜6.85(m, 3H),     7.1˜ (2-15)        1710, 1675. 7.7(m), 8.13, 8.36(2×s, 1H).     8 1:1 O H CH.sub.2 OMe      ##STR59##      1770, 1720, 1685. 2.1˜4.0(m, 2H), 3.30, 3.40(2×s, 3H),     3.74, 3.78(2×s, 3H), 4.1˜5.2(m, 9H), 6.18,6.46(2×s,     1H), 6.61(t, J=7Hz, 0.5H), 6.80, 6.83(2×s, 1H), 7.0˜7.6(m,     20.5H),7.89, 8.24(2×s, 1H). (2-15)

    TABLE 1 (4)      Esters      ##STR60##        cis:    IR (CHCl.sub.3)ν:  Example No trans R R.sup.2 R.sup.5     cm.sup.-1 NMR(CDCl.sub.3)δ: ppm No.       1 1:3 Ph CH.sub.2 H 3390, 1790, 1730, 3.06, 3.37(2×d, J=8Hz,     2H), 3.20˜3.70(m, 2H), 4.92(d, J=5Hz, 1H), 5.10, 5.14 (2-26)     1680, 1630. (2×s, 2H), 5.96(d, J=5Hz, 1H), 6.50˜6.63(m, 1H),     6.92(s, 1H), 7.10˜7.45(m).      2 trans     ##STR61##      CH.sub.2 H 3390, 1785, 1725,1675, 1630, 1495. 3.23(d, J=8Hz, 2H),     3.15˜3.75(m, 2H), 4.94(d, J=5Hz, 1H), 5.12(s, 2H), 5.88,5.98(dd,     J.sub.1 =5Hz, J.sub.2      =10Hz, 1H), 6.36(d, J=10Hz, 1H), 6.52˜6.63(m, 1H), 6.92˜     7.50(m, 20H). (2-28)      3 1:4     ##STR62##      CH.sub.2      ##STR63##      3380, 1785, 1720,1675, 1620. 3.21, 3.54(2×d, J=8Hz, 2H), 3.68(s,     2H), 3.80(s, 3H), 4.22, 4.35(ABq, J=15Hz,2H), 4.96(d, J=5Hz, 1H), 5.11,     5.13(2×s, 2H), 5.86, 5.96(dd, J.sub.1 =5Hz, J.sub.2 =9Hz,1H),     6.34(d, J=9Hz, 1H), 6.90˜7.46(m, 20H). (2-28)      4 5:4     ##STR64##      CH.sub.2 H 3405, 1785, 1730,1682, 1635. 1.49(s, 9H), 3.10˜3.75(m,     2H), 4.95, 4.97(2×d, J=4.5Hz, 1H), 5.93(dd, J.sub.1 =9Hz,J.sub.2     =4.5Hz, 1H), 5.14(s, 2H), 6.50˜6.75(m, 1H), 6.85, 6.97(2×s,     1H), 6.95(s,1H), 7.10˜7.80(m, 17H). (2-10)      5 1:1     ##STR65##      CH.sub.2 H 1790, 1725, 1680,1630. 3.37, 3.72(2×d, J=8Hz, 2H),     3.05˜3.80(m, 2H), 4.96(d, J=5Hz, 1H), 5.13(s, 2H),5.95, 6.04(dd,     J.sub.1 =5Hz, J.sub.2 =9Hz, 1H), 6.55˜6.66(m, 1H), 6.83(t, J=8Hz,     0.5H),6.95(s, 1H), 7.20˜7.50(m, 16.5H), 8.52(d, J=9Hz, 1H), 8.75,     8.84(d, J=2Hz, 1H) (2-7)      6 trans     ##STR66##      CH.sub.2 H 1780, 1720, 1670,1620, 1515, 1340. 3.13˜3.73(m, 2H),     3.50(d, J=7.5Hz, 2H), 5.02(d, J=5Hz, 1H), 5.17(s, 2H), 5.99(dd, J.sub.1     =5Hz, J.sub.2      =8Hz, 1H), 6.57˜6.68(m, 1H), 6.99(s, 1H), 7.2˜7.6(m,     17H),8.07, 8.21(ABq, J=9Hz, 4H), 8.71(d, J=8Hz, 1H), 1H), 9.20(s, 1H).     (2-27)      7 cis     ##STR67##      CH.sub.2 H 1780, 1720, 1665,1625, 1515, 1340. 3.13˜3.75(m, 2H),     3.77(d, J=7Hz, 2H), 5.03(d, J=5Hz, 1H), 5.18(s, 2H), 5.98(dd, J.sub.1     =5Hz, J.sub.2 =8Hz, 1H), 6.60˜6.70(m, 1H), 6.92(t, J=7Hz, 1H),     7.01(s, 1H),7.2˜7.6(m, 16H), 8.09, 8.23(ABq, J=8Hz, 4H), 8.83(d,     J=8Hz, 1H), 9.21(s, 1H). (2-27)      8 1:1     ##STR68##      CH.sub.2 H 1780, 1730, 1540,1280. 3.91˜3.31)m, 1H), 3.64,     3.50(ABq, J=10Hz, 1H), 3.67, 3.81(2×d, J=7Hz, 2H),4.71, 4.84(2.time     s.d, J=5Hz, 1H), 5.04, 5.11(2×s. 1H), 5.22, 5.29(ABq, J=12Hz,     1H),5.22(m, 1H), 5.6˜6.1(m, 0.5H), 6.3˜6.7(m, 1H), 6.22,     6.87(2×s, 1H), 7.2˜7.7(m,23H), 8.33, 9.07(2×d, J=8Hz,     1H). (2-1)      9 cis     ##STR69##      -- H 3200, 1770, 1730,1690, 1550, 1290. 2.78˜3.24(m, 2H), 4.88(d,     J=5Hz, 1H), 5.11(s, 2H), 5.17, 5.32(ABq, J=13Hz,2H), 6.09, 6.19(dd,     J.sub.1 =8Hz, J.sub.2 = 5Hz, 1H),6.52(m, 1H), 6.86(s, 1H), 7.01(s,     1H),7.27(m, 20H), 8.46(d, J=8Hz, 1H). (2-1)

    TABLE 2(1)      Carboxylic acids      ##STR70##       No. cis:trans R.sup.3 R.sup.5 R.sup.8 IR ν : cm.sup.-1 NMR δ:     ppm Example No.        1 1:1 H H H 1763, 1705, 1630 3.22(d, J=7Hz, 1H), 3.42(d, J=7Hz, 1H),     3.60(s, 2H), 5.07, 5.11(2×d, J=5Hz, 1H), 3-(1),      [KBr].     5.81(d, J=5Hz, 1H), 6.31, 6.57(2×s, 1H), 6.3˜6.8(m, 2H)     [CD.sub.3 COCD.sub.3CD.sub.3 ODD.sub.2 O]. 4-(1).  2 cis H H (HCl salt)     H 3425, 3300, 3260, 3.31(d, J=7Hz, 2H), 3.54˜3.63(brs, 2H),     5.21(d, J=5Hz, 1H), 5.79(d, J=5Hz, 1H), 6.54 3-(1).(2),      1760, 1715,     1657, ˜6.83(m, 2H), 6.63(s, 1H) [CD.sub.3 SOCD.sub.3CD.sub.3 OD].     4-(1).(2),      1620, 1548 [Nujol]  9.  3 cis H H H 3580, 3260, 1770,     3.68(d, J=8Hz, 2H), 3.9(A part of ABX, J.sub.1 =5.5Hz, J.sub.2 =20Hz,     1H), 4.13(B part of ABX, 1-(4),      1700, 1650, 1572, J.sub.1 =3.5Hz,     J.sub.2 =20Hz, 1H), 5.65(d, J=5Hz, 1H), 6.30(d, J=5Hz, 1H), 6.78(X part     of ABX, (3-(1),      1546, 1362 [Nujol] J.sub.1 =3.5Hz, J.sub.2 =5.5Hz,     1H), 6.95(t, J=8Hz, 1H), 7.05(s, 1H) [NaHCO.sub.3D.sub.2 O]. 4-(1), 8.     4 1:1 H Me H 1760, 1710, 1630 2.13(s, 3H), 3.39(d, J=7Hz, 2H), 5.03(d,     J=4.5Hz, 1/2H), 5.08(d, J=4Hz, 1/2H), 5.73(d, 1-(4),      [KBr].     J=4.5Hz), 5.76(d, J=4Hz, 1/2H), 6.43, 6.54(2×s, 1H), 6.61,     6.94(2×t, 7Hz, 1H) 3-(2),       [CD.sub.3 SOCD.sub.3CD.sub.3     ODCDCl.sub.3 ]. 4-(2).  5 1:1 H CH CH.sub.2 H 3280, 1760, 1630 3.66(d,     J=8Hz, 2H), 4.10(brs, 2H), 5.62˜5.96(m, 3H), 6.16, 6.22(2×d,     J=4Hz, 1H), 1-(4),      [Nujol]. 6.85˜7.46(m, 3H) [D.sub.2 O].     3-(2)        4-(2).      6 1:1 H CHCHCN (Z) H 3195, 2205, 1764, 3.3˜4.2(m, 4H), 5.08,     5.15(2×d, J=4.5Hz, 1H), 5.26(d, J=12Hz, 1H), 5.63, 5.71(2×d,     1-(1),      1611 [Nujol]. J=4.5Hz, 1H), 6.35, 6.43(2×s, 1H), 6.53,     6.78(m, 1H), 6.98(d, J=12Hz, 1H) [NaHCO.sub.3D.sub.2 O]. 3-(2),     4-(2).  7 1:1 H CHCHCOOH (E) H 3267, 1770, 1612 2.8˜3.4(m, 2H),     3.42, 3.72(ABq, J=14.5Hz, 2H), 5.10 5.15(2×d, J=4.5Hz, 1H), 5.63,     1-(4),      [Nujol]. 5.69(2×d, J=4.5Hz, 1H), 5.90(d, J=16Hz, 1H),     6.36, 6.76(2×m, 1H), 6.45, 6.53(2×s, 3-(2),       1H),     7.23(d, J=16Hz, 1H)[NaHCO.sub.2D.sub.2 O]. 4-(2).  8 1:1 H CHCHCF.sub.3     (1Z:2E) H 3340, 1770, 1708, 3.67(d, J=7.8Hz, 2H), 3.75˜ 4.3(m,     2H), 5.67, 5.73(2×d, J=4.5Hz, 1H); 6.15˜6.70(m, 1-(4),     1640, 1530 [KBr]. 2H), 6.96, 7.24(2×t, 7.8Hz, 1H), 7.05, 7.13(2.tim     es.s, 1H), 7.20, 7.68(2×d, J=10Hz, J= 3-(2),       16.5Hz,     1H)[NaHCO.sub.3D.sub.2 O] 4-(2).  9 1:1 H CHCHCF.sub.3 (Z) H 3360, 1772,     1708, 3.68(d, J=7.8Hz, 2H), 3.99, 4.19(ABq, J=18Hz, 2H), 5.18 5.73(2.time     s.d, J=4.5Hz, 1H), 1-(4),      1655, 1628, 1532 6.17, 6.27(2×d,     J=4.5Hz, 1H), 6.1˜6.7(m, 1H), 7.05, 7.34(2×t, 7.8Hz, 1H),     7.07, 7.15 3-(2),      [KBr]. (2×s, 1H), 7.23(d, J=12.8Hz, 1H)     [NaHCO.sub.3D.sub.2 O]. 4-(2). 10 1:2 H CH.sub.2 N ⊕ C.sub.5 H.sub.5     ⊖ 3380, 1770, 1620, 3.66, 4.08(ABq, J=18Hz, 2H), 3.78(d, J=8Hz,     2H), 5.66, 5.71(2×d, J=5Hz, 1H), 5.80 3-(7),      1525 [KBr].     6.00(ABq, J=15Hz, 2H), 6.20, 6.26(2×d, J=5Hz, 1H(, 7.11, 7.24(2.tim     es.s, 1H), 6.8˜7.5(m, 4-(2)       1H), 8.4˜9.5(m, 5H)     [D.sub.2 O]. 11 2:3 H CH.sub.2 OMe H 3170br, 1760, 1622 nd 1-(4),     [Nujol].  3-(2),        4-(2). 12 3:5 H CH.sub.2 OCOMe H 3275, 1770,     1720, 2.75(s, 3H), 3.70(d, J=8Hz, 2H), 3.86, 4.13(ABq, J=18Hz, 2H),     5.60, 5.70(2×d, J=6Hz, 1-(4),      1630 [Nujol]. 1H), 6.22,     6.28(2×d, J=6Hz, 1H), 6.98, 7.38(2×t, J=8Hz, 1H), 7.07,     7.16(2×s, 1H) 3-(2),       [NaHCO.sub.3D.sub.2 O] 4-(2). 13 2:3 H     CH.sub.2 OCONH.sub.2 H 3250, 1760, 1720, 3.66(d, J=8Hz, 2H), 3.83,     4.08(ABq, J=18Hz, 2H), 5.12, 5.31(ABq, J=12Hz, 2H), 5.61, 1-(4),     1700 [Nujol]. 5.67(2×d, J=4Hz, 1H), 6.19, 6.24(2×d, J=4Hz,     1H), 7.00, 7.14(2×s, 1H), 6.95, 7.36 3-(2),       (2×t,     J=8Hz, 1H), [NaHCO.sub.3D.sub.2 O]. 4-(2). 14 1:1 Na CH.sub.2 SMe Na     3370, 1755, 1590, 2.46(s, 3H), 3.67(d, J=8Hz, 2H), 3.7˜4.3(m, 4H),     5.62(d, J=5Hz, 1/2 H), 5.66(d, J=4Hz, 1-(2),      1525 [KBr]. 1/2H),     6.12(d, J=5Hz, 1/2H), 6.17(d, J=4Hz, 1/2H), 6.94, 7.35(2×t, J=8Hz,     1H), 7.05, 3-(2),       7.14(2×s, 1H)[D.sub.3 O]. 4-(2). 15  H     CH.sub.2 SCH.sub.2 CN H 3300, 2240, 1765, 3.68(d, J=8Hz, 2H), 3.91,     4.20(ABq, J=13Hz, 2H), 4.01(s, 2H), 4.20(s, 2H), 5.65, 1-(4),      1625.     1530 [Nujol]. 5.71(2×d, J=5Hz, 1H), 6.19, 6.23(2×d, J=5Hz,     1H), 6.97, 7.38(2×t, J=8Hz, 1H), 7.07, 3-(2),       7.15(2×s,      1H) [NaHCO.sub.3D.sub.2 O]. 4-(2). 16  H CH.sub.2 SCHF.sub.2 H 3275br,     1765, 1660 nd 1-(4),      sh, 1625 [Nujol].  3-(2),        4-(2).  17     2:3 Na      ##STR71##      Na 1748 [Nujol]. 3.67(d, J=8Hz, 2H), 3.65˜4.37(m, 2H), 4.50,     4.71(ABq, J=21Hz, 1H), 5.54, 5.59(2×dJ=4.5Hz, 1H), 6.09, 6.15(2.tim     es.d, J=4.5Hz, 1H), 6.95, 7.35(2×t, J=8Hz, 1H), 7.04, 7.14(2×     s, 1H), 8.41(s, 1H) [D.sub.2 O]. 1-(1),3-(2),4(2).      18 3:5 Na     ##STR72##      Na 1770, 1662, 1630[KBr]. 3.60, 3.69(2×d, J=7Hz, 2H), 3.91˜4     .10(m, 2H), 4.17˜4.41(m, 2H), 5.04, 5.61(2×d, J=5Hz, 1H),     6.10, 6.17(2×d, J=5Hz, 1H), 6.93, 7.33(2×t, J=7Hz, 1H),     7.03, 7.12(2×s,1H), 9.15(s, 1H) [Na-salt-D.sub.2      O]. 1-(1),3-(2),4-(2)      19 1:1 H     ##STR73##      H 3300, 1764, 1627,1529, 1367 [KBr]. 3.69(d, J=8Hz, 2H), 4.07(ABq,     J=17Hz, 2H), 4.75(ABq, J=12Hz, 2H), 5.58, 5.62(2×d, J= 4Hz, 1H),     6.18, 6.20(d, J=4Hz, 1H), 6.98, 7.40(2×t, J=8Hz, 1H), 7.03,     7.13(2×s, 1H),9.88(s, 1H) [NaHCO.sub.3D.sub.2      O]. 1-(4),3-(2),4-(2).      20 1:1 H     ##STR74##      H 3390, 1763, 1622,1523, 1376 [KRr]. 3.18(s, 3H), 3.68(d, J=8Hz, 2H),     4.03(ABq, J=17Hz, 2H), 4.67(ABq, J=14Hz, 2H), 5.57,5.61(2×d,     J=4Hz, 1H), 6.14, 6.17(2×d, J=4Hz, 1H), 6.94, 7.37(2×t,     J=8Hz, 1H), 7.01,7.11(2×s, 1H) [NaHCO.sub.3D.sub.2                 4      O]. 1-(4),3-(2),-(2).      21 1:1 H     ##STR75##      H 3300, 1763, 1621,1511, 1382, 1355[KBr]. 3.69(d, J=8Hz, 2H), 4.16(ABq,     J=ABq, J=18Hz, 2H), 4.53(ABq, J=13.5Hz, 2H), 5.58, 5.62(2×dJ=4Hz,     1H), 6.14, 6.19(2×d, J=4Hz, 1H), 6.97, 7.38(2×t, J=8Hz, 1H),     7.04, 7.13(2×s,1H) [NaHCO.sub.3D.sub.2 O]. 1-(4),3-(2),4-(2).  22     1:1 H      ##STR76##      H 3410, 1762, 1615,1528, 1361 [KBr]. 3.68(d, J=9Hz, 2H), 4.06(ABq,     J=18Hz, 2H), 4.65(ABq, J=14Hz, 2H), 4.87, 5.01(2×s,2H), 5.58,     5.62(2×d, J=4Hz, 1H), 6.14, 6.19(2×d, J=4Hz, 1H), 6.70˜     7.50(m, 1H), 7.04,7.13(2×s, 1H) [NaHCO.sub.3D.sub.2      O]. 1-(4),3-(2),4-(2).      23 1:1 H     ##STR77##      H 1765, 1710, 1630,[KBr]. 3.37(d, J=8Hz, 2H), 3.69(s, 2H), 3.95(s, 3H),     4.35(s, 2H), 5.03, 5.07(2×d, J=5Hz,1H), 5.82(d, J=5Hz, 1H), 6.41,     6.53(2×s, 1H), 6.61, 6.93(2×t, J=8Hz, 1H)[CD.sub.3           C      SOCD.sub.3D.sub.3 ODCDCl.sub.3 ]. 1-(4)3-(6).  24 3:5 H OMe H 3275,     1760, 1620 3.68, 3.72(2×d, J=8Hz, 2H), 3.73˜4.25(m, 2H),     4.21, 4.23(2×s, 3H), 5.64, 5.70(2×d, 1-(4),      [Nujol].     J=6Hz, 1H), 6.00, 6.05(2×d, J=6Hz, 1H), 6.97, 7.37(2×t,     J=8Hz, 1H), 7.10, 7.16(2×s, 3-(2),       1H)[NaHCO.sub.3D.sub.2     O]. 4-(2). 25 3:5 H Cl H 3275, 1760, 1625 3.64, 3.65(2×d, J=8Hz,     1H), 3.97, 4.34:4.00, 4.37(2×ABq, J=18Hz, 2H), 5.68, 5.71(2×     1-(4),      [Nujol]. d, J=6Hz, 1H), 6.17, 6.22(2×d, J=6Hz, 1H),     6.94, 7.33(2×t, J=8Hz, 1H), 7.03, 7.13(2× 3-(2),       s,     1H)[NaHCO.sub.3D.sub.2 O]. 4-(2). 26 1:2 H SCH.sub.2 CH.sub.2 F H 3300,     1763, 1660, 3.52(dt, J.sub.1 =22.5Hz, J.sub.2 =6Hz, 2H), 3.67(d,     J=7.5Hz, 2H), 3.83, 4.41(ABq, J=17.1Hz, 1-(4),      1629, 1531 [KBr].     2H), 5.07(dt, J.sub.1 =47.7Hz, J.sub.2 =6Hz, 2H), 5.63, 5.69(2×d,     J=5Hz, 1H), 6.15, 6.21(2×d, J= 3-(4),       5Hz, 1H), 6.96,     7.36(2×t, J=7.5Hz, 1H), 7.06, 7.15(2×s, 1H) [NaHCO.sub.3D.sub     .2 O]. 3-(5). 27 3:7 Na SCH.sub.2 CF.sub.3 Na nd 3.70(d, J=7Hz, 2H),     3.6˜4.4(m, 2H), 4.30, 4.85(ABq, J=15Hz, 2H), 5.67, 5.74(2×d,     J= 3-(2),(4),       4Hz, 1H), 6.20, 6.27(2×d, J=4Hz, 1H), 7.00,     7.38(2×t, J=7Hz, 1H), 7.07, 7.17(2×s, 1-(2).       1H)     [D.sub.2 O]. 28 4:5 H SCHCH.sub.2 H 3150, 1760, 1705 3.68(d, J=7Hz, 2H),     4.15(brs, 2H), 5.6˜6.2(m, 1H), 6.35(q, J.sub.1 =16Hz, J.sub.2     =8Hz, 1H), 1-(4),      [Nujol]. 6.8˜7.6(m, 2H) [NaHCO.sub.3D.sub.2     O]. 3-(4).

    TABLE 2(2)       Carboxylic acids      ##STR78##       No. cis: trans R.sup.1 R.sup.2 R.sup.3 R.sup.5 R.sup.6 IR (KBr)ν:     cm.sup.-1 NMR δ: ppm Example No.       1 cis H -- H Me H nd 2.17(s, 3H), 5.08(d, J=4.5Hz, 1H), 5.78(d,     J=4.5Hz, 1H), 6.50(s, 1H), 6.86 1-(4), 3-         (s, 1H) [CDCl.sub.3CD.s     ub.3 OD]. (2), 4-(2) 2 cis H -- h CHCH.sub.2 H 1765, 1700sh, 1650 3.60,     3.74(ABq, J=17Hz, 2H), 5.17(d, J=5Hz, 1H), 5.32(d, J=11Hz, 1H), 5.53     1-(4),        1615. (d, J=17Hz, 1H), 5.83(d, 5Hz, 1H), 6.50(s, 1H),     6.81(s, 1H), 7.12(dd, J.sub.1 = 3-(2),         11Hz, J.sub.2 =17Hz, 1H)     [CDCl.sub.3CD.sub.3 SOCD.sub.3CD.sub.3 OD]. 4-(2). 3 cis H -- H CH.sub.2     OCOMe H 1779, 1717, 1615. 2.10(s, 3H), 6.55(s, 1H), 6.87(s, 1H) [CDCl.sub     .3CD.sub.3 OD]. 1-(4), 3-          (2), 4-(2) 4 trans H -- H CH.sub.2     OCOMe H 1780, 1730, 1650. 2.10(s, 3H), 5.73(d, J=5Hz, 1H), 6.17(s, 1H),     6.97(s, 1H) [CDCl.sub.3CD.sub.3 OD]. 1-(4), 3-          (2), 4-(2) 5 cis     H CH.sub.2 CH.sub.2 Na H Na 3300, 3200, 2900, 2.88(m, 4H), 4.05(m, 2H),     5.65(d, J=6.0Hz, 1H), 6.28(d, J=6.0Hz, 1H), 6.75 1-(1),        1755,     1650, 1600, (m, 1H), 7.00(s, 1H), 7.22(m, 1H) ]D.sub.2 O]. 3-(2),     1550, 1410, 1360.  4-(2). 6 trans H CH.sub.2 CH.sub.2 Na H Na 3300,     3200, 2900, 2.89(m, 4H), 4.00(m, 2H), 5.56(d, J=6.0Hz, 1H), 6.20(d,     J=6.0Hz, 1H), 6.75 1-(1),        1755, 1650, 1600, (m, 1H), 7.18(s, 1H),     7.25(m, 1H) [D.sub.2 O]. 3-(2),        1550, 1410, 1360.  4-(2). 7 1:1 H     >CHMe Na H Na 3380, 1758, 1640, 1.70, 173(2×d, J=7Hz, 3H),     3.5˜4.5(m, 3H), 5.57, 5.63(2×d, J=5Hz, 1H), 6.16 1-(2),       1580. ˜6.32(m, 1H), 6.67˜6.83(m, 1H), 6.83, 7.24(2×d,      J=11Hz, 1H), 7.01, 7.11(2×s, 1H) [D.sub.2 O]. 3-(2).     4-(2) 8 exo H >CHMe Na H Na 3380, 1758, 1645, 2.31(brs, 3H), 3.7˜4.     3(m, 2H), 5.51(d, J=5Hz, 1H), 6.12(d, J=5Hz, 1H), 6.68˜ 1-(2), 3-           1595. 6.77(m, 1H), 6.89˜7.05(m, 2H) [D.sub.2 O]. (2), 4-(2)     9 trans H (CH.sub.2).sub.3 Na H Na 3300, 3200, 2900, 2.15(m, 2H),     2.64(m, 4H), 4.00(m, 2H), 5.55(d, J=6.0Hz, 1H), 6.20(d, J=6.0 1-(1),        1760, 1655, 1600, Hz, 1H), 6.75(m, 1H)7.10(s, 1H), 7.29(m, 1H)     [D.sub.2      O]. 3-(2),        1550, 1410, 1360.  4-(2). 10 cis H (CH.sub.2).sub.3     Na H Na 3300, 3200, 2900, 2.15(m, 2H), 2.70(m, 4H), 4.01(m, 2H), 5.62(d,     J=6.0Hz, 1H), 6.26(d, J=6.0 1-(1),        1760, 1655, 1600, Hz, 1H),     6.75(m, 1H), 6.97(s, 1H), 7.29(m, 1H) [D.sub.2 O]. 4-(2).        1550,     1410, 1360.  (2), 4-(2) 11 cis H >CMe.sub.2 Na H Na 3400, 1760, 1690,     1.83(s, 6H), 3.7˜4.3(m, 2H), 5.63(d, J=5Hz, 1H), 6.28(d, J=5Hz,     1H), 6.7˜6.8 1-(1), 3-        1570. (m, 1H), 6.99(s, 2H) [D.sub.2     O]. (2), 4-(2) 12 trans H >CMe.sub.2 Na H Na 3400, 1758, 1600sh 1.63(s,     3H), 1.06(s, 3H), 3.74˜4.30(m, 2H), 5.60(d, J=5Hz, 1H), 6.23(d,     J=5 1-(2), 3-        1600. Hz, 1H), 6.73˜6.83(m, 1H), 7.08(s, 1H),     7.47(s, 1H) [D.sub.2 O]. (2), 4-(2) 13 cis H CD.sub.2 Na H Na 3580,     3260, 1770, 3.70˜4.35(m, 2H), 5.65(d, J=5Hz, 1H), 6.29(d, J=5Hz,     1H), 6.73˜6.83(m, 1H), 1-(2),        1700, 1650, 1620, 6.95(s,     1H), 7.06(s, 1H) [D.sub.2 O]. 3-(2),        1570, 1545 [Nujol]  4-(2).     14 1:1 Cl -- H H H nd 3.40˜3.70(m, 2H), 5.13(d, J=5Hz, 1H),     5.91(d, J=5Hz, 1H), 6.5˜6.7(m, 1H), 1-(4), 3-         6.50,     6.83(2×s, 1H) [CD.sub.3 OD]. (2), 4-(2) 15 1:1 Cl (CH.sub.2).sub.2     H H H 3300, 1765, 1720, 2.8˜3.15(m, 2H), 3.2˜3.55(m, 2H),     3.75˜4.3(m, 2H), 5.62(d, J=4.5Hz, 1H), 1-(4),        1627, 1530.     6.16, 6.23(2×d, J=4.5Hz, 1H), 7.65˜7.9(m, 1H), 7.19,     7.49(2×s, 1H) [D.sub.2 ONaHCO.sub.3 ] 3-(2),          4-(2). 16     10:1 Cl (CH.sub.2).sub.3 Na H Na nd 2.20˜3.30(m, 6H), 3.85˜4.     15(m, 2H), 5.62(d, J=3Hz, 1H, 6.23(d, J=3Hz, 1H), 1-(2), 3-     6.75(brs, 1H), 7.15, 7.55(2×s, 1H) [D.sub.2 O] . (2), 4-(2) 17  Cl     SCH.sub.2 H H H nd 3.8˜4.3(m, 2H), 4.14(s, 2H), 5.61(d, J=4.5Hz,     1H), 6.24(d, J=4.5Hz, 1H), 1-(4), 3-         6.74(t, J=3Hz, 1H), 7.44(s,     1H) [D.sub.2 ONaHCO.sub.3      ]. (2), 4-(2)

    TABLE 2      Carboxylic acids      ##STR79##        cis:        IR(KBr)ν:  Example No. trans X R.sup.1 R.sup.2 R.sup.3     R.sup.4 R.sup.5 R.sup.8 cm.sup.-1 NMR δ(D.sub.2      O): ppm No.          18 1:2 SO H CH.sub.2 Na H H Na 3400, 1775, 1600,     3.65(brd, J=8Hz, 2H), 3.85˜4.15(m, 1H), 4.65˜5.0(m, 1H),     5.34, 5.43 1-(1),   α       1525, 1410, 1360. (2×d, J=5Hz,     1H), 6.11, 6.23(2×d, J=5Hz, 1H), 6.49˜6.62(m, 1H), 6.99,     3-(2),           7.37(2×t, J=8Hz, 1H), 7.03, 7.13(2×s, 1H).     4-(2). 19 1:1 SO H CH.sub.2 Na H H Na 3400, 1770, 1600, 3.65, 3.67(2.time     s.d, J=8Hz, 2H), 5.42, 5.46(2×d, J=4Hz, 1H), 6.47, 6.53(2×     1-(2),   β       1525, 1410, 1360. d, J=4Hz 1H), 6.55˜6.62(m,     1H), 6.97, 7.52(2×t, J=8Hz, 1H), 7.06, 3-(2),           7.14(2.time     s.s, 1H). 4-(2). 20 2:3 O H CH.sub.2 Na OMe CHCH.sub.2 Na nd 3.70(d,     J=8Hz, 2H), 4.00, 4.08(2×s, 3H), 5.0˜5.3(m, 2H), 5.55˜5     .90(m, 1-(2), 3-           3H), 6.94, 7.40(2×t, J=8Hz, 1H), 7.07,     7.14(2×s, 1H), 7.0˜7.50(m, 1H), (2), 4-(2)  21 1:1 O H     CH.sub.2 H OMe      ##STR80##      H 1773, 1670, 1630. nd 1-(4), 3-(2), 4-(2)  22 1:1 O H CH.sub.2 Na OMe      ##STR81##      Na nd 3.70(d, J=8Hz, 2H), 3.99, 4.07(2×s, 3H), 4.50(s, 3H), 5.63,     5.68(2×s,1H), 6.95, 7.43(2×t, J=8Hz, 1H), 7.05, 7.13(2×     s, 1H). 1-(2), 3-(2), 4-(2)

    TABLE 2      Carboxylic acids      ##STR82##        cis:      IR (KBr)ν:  Example No. trans R R.sup.2 R.sup.3 R.sup.5     R.sup.8 cm.sup.-1 NMR δ: ppm No.       1 trans Ph CH.sub.2 Na H Na 3400, 1760, 1650, 3.47(d, J=8Hz, 2H),     3.65˜4.25(m, 2H), 5.55(d, J=5Hz, 1H), 6.15(d, J= 1-(2),     1585, 1510, 1410, 5Hz, 1H), 6.66˜6.76(m, 1H), 7.30(t, J=8Hz, 1H),     7.66˜8.05(m, 5H) 3-(2).        1365. [D.sub.2 O].  2 trans      ##STR83##      CH.sub.2 Na H Na 3395, 1760, 1650,1585, 1510, 1410,1365. 3.70(d, J=     8Hz, 2H), 3.60˜4.26(m, 2H), 5.56(d, J=5Hz, 1H), 6.16(d, J=5Hz,     1H), 6.70˜6.80(m, 1H), 7.25(t, J=8Hz, 1H), 7.45˜7.65(m,     2H),7.96˜8.05(m, 1H) [D.sub.2 O]. 1-(2),3-(2).      3 2:8     ##STR84##      CH.sub.2 Na      ##STR85##      Na 3400, 1760, 1660,1590, 1385. 3.66, 3.72(2×d, J=8Hz, 2H), 3.90,     4.22(ABq, J=18Hz, 2H), 4.47(s, 3H)4.43, 4.81(ABq, J=14Hz, 2H), 5.56,     5.62(2×d, J=5Hz, 1H), 6.08, 6.20,(2×d, J=5Hz, 1H), 6.80,     7.26(2×t, J=8Hz, 1H), 7.5˜8.05(m, 3H). 1-(2),3-(2).  4 2:1      ##STR86##      CH.sub.2 Na H Na 3420, 1760, 1655,1585, 1413, 1365. 3.63, 3.76(2×d     , J=8Hz, 2H), 3.73˜4.33(m, 2H), 5.66(d, J=5Hz, 1H),6.22, 6.32(2.tim     es.dd, J.sub.1 =5Hz, J.sub. 2 =9Hz, 1H), 6.7˜6.83(m, 1H), 7.18,     7.43(2×t, J=8Hz, 1H), 8.02 8.11(2×d, J=2Hz, 1H), 9.43,     9.51(2×d, J=2Hz,1H) [D.sub.2 O]. 1-(2)3-(2).      5 5:4     ##STR87##      CH.sub.2 H H H 3450, 3360, 1772,1717, 1670, 1630,1520. 3.45, 3.57(2.time     s.d, J=7.5Hz, 2H), 2H), 3.3˜3.8(m, 2H), 5.10, 5.13(2×d,J=4.5H     z, 1H), 5.80, 5.86(2×d, J=4.5, 1H), 6.55˜6.75(m, 1H),     6.65,6.80(2×s, 1H), 6.67, 6.78(2×t, J=7.5Hz, 1H) [CD.sub.3     OD]. 1-(4),3-(2),4-(2).      6     ##STR88##      CH.sub.2 Na H Na 3400, 1758, 1655,1590, 1365. 3.76, 3.81(2×d,     J=7Hz, 2H), 4.02(m, 2H), 5.63, 5.58(2×d, J=5Hz, 1H),6.23, 6.32(2.ti     mes.d, J=5Hz, 1H), 6.76(m, 1H), 7.50, 7.56(2×t, J=7Hz, 1H) [D.sub.2      O]. 1-(2),3-(2),4-(2).      7     ##STR89##      -- H H H 3352, 1773, 1716. nd 1-(4),3-(2),4-(2).

    TABLE 3      Pharmaceutical esters      ##STR90##        cis:    IR(CHCl.sub.3) ν:  Example No. trans R.sup.0 R.sup.3     R.sup.8 cm.sup.-1 NMR(CDCl.sub.3) δ: ppm No.       1 cis H H POM 3420, 2980, 1780, 1.20(s, 9H), 3.15˜3.75(m, 4H),     5.04(d, J=5Hz, 1H), 5.81, 5.92(ABq, J=6Hz, 2H), 5.90(d, 3-(2),     1750, 1660, 1630, J=5Hz, 1H), 6.40˜6.70(m, 2H), 7.35(s, 1H).     4-(2),      1530, 1480, 1390[KBr].  5-(2). 2 1:1 H H POM 3420, 2980,     1780, 1.20(s, 9H), 3.15˜3.75(m, 4H), 5.04, 5.06(2×d, J=5Hz,     1H), 5.81, 5.92(ABq, J=6Hz, 2H), 3-(2),      1750, 1660, 1630, 5.85.about     .5.95(m, 1H), 6.40˜6.70; 6.83˜7.03(2×m, 2H), 7.37(s,     1H) [CDCl.sub.3 --CD.sub.3 OD]. 4-(2),      1530, 1480, 1390[KBr].     5-(2). 3 1:1 H POM POM 3395, 3320, 1790, nd 4-(3),      1753, 1685,     1110,  5-(2).      988. 4 1:1 H AOM AOM 3380, 3310, 1790, nd 4-(2),     1741, 1687, 1150,  5-(5).      985. 5 1:1 Cbz Bzl POM nd 1.20(s, 9H),     3.00˜3.90(m, 4H), 5.13(s, 2H), 5.10, 5.33; 5.15, 5.37(2×ABq,     J=12Hz, 2H), 4-(2).       5.55˜6.00(m, 3H), 5.85, 5.92(2×d,     J=5Hz, 1H), 6.36˜6.53(m, 1H), 6.65, 7.07(2×t, J=8Hz,     1H), 6.94, 6.96(2×s, 1H), 7.20˜7.50(m, 10H), 7.66, 8.05(2.tim     es.d, J=8Hz, 1H).

                                      TABLE 4                                     __________________________________________________________________________    Side chain fragment acids and derivatives                                      ##STR91##                                                                    R         R.sup.1                                                                           R.sup.2                                                                           IR(Nujol)ν:cm.sup.-1                                                                   NMR δ: ppm                                __________________________________________________________________________    1  BOC    H   H   3120, 1700, 1675.                                                                         1.50(s, 9H), 3.45(d, J=7.5Hz, 2H), 7.00(t,                                    J=7.5                                              (cis)          dp 153˜154° C.                                                               Hz, 1H), 7.13(s, 1H) [CD.sub.3 SOCD.sub.3                                     ].                                              2  BOC    H   H   3150, 1700, 1630,                                                                         1.49(s, 9H), 3.41(d, J=7.5Hz, 2H), 6.89(t,                                    J=7.5                                              (trans)        1600.       Hz, 1H), 7.08(s, 1H) [CD.sub.3 SOCD.sub.3                                     ]                                                                 dp 165˜167° C.                                 3  Cbz    H   H   3200, 1738, 1715,                                                                         3.44, 3.50, (2×d, J=8Hz, 2H), 5.25(s,                                   2H), 7.07,                                                        1690.       7.35(2×t, J=8Hz, 1H), 7.12(s, 1H),                                      7.38(brs, 5H)                                                     dp 169˜172° C.                                                               [CDCl.sub.3CD.sub.3 OD]                         4  HCO    H   H   3400, 1718, 1690,                                                                         3.45, 3.63(2× d, J=7.5Hz, 2H), 7.14,                                    7.32(2×t, J=                                                1630, 1550. 7.5Hz, 1H), 7.23, 7.25(2×s, 1H),                                        8.51(s, 1H)                                                       dp 168° C.                                                                         [CDCl.sub.3CD.sub.3 OD].                        5  ClCH.sub.2 CO                                                                        H   H   3100, 1720, 1685,                                                                         3.45(d, J=8Hz, 2H), 4.37(s, 2H), 6.97,                                        7.05(2×t,                                                   1620.       J=8Hz, 1H), 7.23, 7.27(2×s, 1H)                                         [CD.sub.3 SOCD.sub.3 ].                                           dp 153-155° C.                                       6  BOC    H   Bzl 3160, 1740, 1724,                                                                         3.95(d, J=7.5Hz, 2H), 5.50(s, 2H), 7.26(t,                                    J=7.5                                                             1700, 1678, 1255,                                                                         Hz, 1H), 7.30(brs, 1H), 7.49(s, 1H),                                          7.75(s,                                                           1168.       5H), 11.86(brs, 1H) [CD.sub.3 SOCD.sub.3                                      ].                                              7  HCO    H   t-Bu                                                                              3150, 3100, 1720,                                                                         1.40(s, 9H), 3.43(d, J=7Hz, 2H), 6.89,                                        7.00(2×t,                                    (1 cis:        1690, 1635. J=7Hz, 1H), 7.20, 7.26(2×s, 1H),                                        8.48(s, 1H)                                        2 trans)       mp. 185˜188° C.                                                              [CD.sub.3 SOCD.sub.3 ].                         8  HCO    H   Bzl 1735, 1680, 1620,                                                                         3.69(d, J=7Hz, 2H), 5.12(s, 2H), 7.17(t,                                      J=7Hz,                                                            dp 153˜ 155° C.                                                              1H), 7.21(s, 1H), 7.32(s, 5H), 8.46(s, 1H)                                    [CD.sub.3 SOCD.sub.3 ].                         9  ClCH.sub.2 CO                                                                        H   Me  nd          3.39(d, J=7.5Hz, 2H), 3.70(s, 3H), 4.24(s,                                    2H),                                                                          7.11(s, 1H), 7.23(t, J=7.5Hz, 1H),                                            9.37(brs,                                                                     2H) [CDCl.sub.3 ].                              10 ClCH.sub.2 CO                                                                        H   Bzl 1726, 1685, 1160.                                                                         3.95, 4.01(2×d, J=7.5Hz, 2H), 4.71(s,                                   2H), 5.45,                                                        dp 155° C.                                                                         5.47(2×s, 2H), 7.28, 7.40(2×t,                                    J=7.5Hz, 1H),                                                                 7.58, 7.65(2×s, 1H), 7.70(s, 5H),                                       12.9(brs, 1H)                                                                 [CD.sub.3 SOCD.sub.3 ].                         11 Cbz    H   Me  3400˜2300, 1740,                                                                    3.58˜3.73(m, 2H), 3.63(s, 3H),                                          5.27(s, 2H), 7.03                                                 1550.       ˜7.46(m, 7H) [CD.sub.3 SOCD.sub.3 ].      12 Cbz    H   t-Bu                                                                              3160˜2200, 1720,                                                                    1.42(s, 9H), 3.53(d, J=7Hz, 2H), 5.29(s,                                      1H),                                               (trans)        1680, 1635. 7.27(t, J=7Hz, 1H), 7.35(s, 1H),                                              7.30˜7.50(m,                                                mp. 169˜171° C.                                                              5H) [CD.sub.3 COCD.sub.3 ].                     13 Cbz    H   t-Bu                                                                              nd          1.44(s, 9H), 3.53(d, J=7Hz, 2H), 5.27(s,                                      2Hz,                                               (cis)                      7.13(t, J=7Hz, 1H), 7.24(s, 1H),                                              7.30˜7.47(m,                                                            5H) [CDCl.sub.3 ].                              14 Cbz    H   Me  3150˜2050, 1720,                                                                    2.33(s, 3H), 2.53, 2.70(2×d, J=8Hz,                                     2H), 5.11(s,                                       (2 cis:    Bzl 1670, 1620, 1570.                                                                         2H), 5.26(s, 2H), 6.99˜7.40(m, 10H)                                     [CDCl.sub.3                                        1 trans)       mp. 160˜163° C.                                                              CD.sub.3 OD].                                   15 Cbz    H   Bzl 1725, 1675, 1620,                                                                         3.51, 3.73(2×d, J=7Hz, 2H), 5.13(s,                                     2H), 5.26                                          (2 cis:        1575.       (s, 2H), 7.06, 7.10(2×s, 1H),                                           7.0˜7.5(m, 11H)                              3 trans)       mp. 164˜166° C.                                                              [CDCl.sub.3CD.sub.3 OD].                        16 Cbz    H   PMB 1720, 1575, 1515.                                                                         3.80(d, J=8Hz, 2H), 3.90(s, 3H), 5.20(s,                                      2H),                                                              mp. 145˜148° C.                                                              5.33(s, 2H), 7.00(s, 1H),                                                     6.85˜7.60(m, 10H)                                                       [CDCl.sub.3CD.sub.3 OD].                        17 H      Me  H   3330˜2450, 1720,                                                                    3.39(d, J=7Hz, 2H), 3.73(s, 3H), 6.88(s,                                      1H),                                               (HClsalt)      1680, 1630. 7.25(t, J=7Hz, 1H) [ CD.sub.3 SOCD.sub.3                                      ].                                              18 Cbz    H   CH.sub.2                                                                          3515, 2480(br),                                                                           3.35(d, J=8Hz, 4/3H), 3.68(d, J=8Hz, 2/3H),                                   4.56                                               (1 cis:    CH  1736, 1549, 1305,                                                                         (d, J=6Hz, 2H), 5.11˜5.37(m, 4H),                                       5.65˜6.15(m,                                 2 trans)   CH.sub.2                                                                          1086 (CHCl.sub.3).                                                                        1H), 6.90˜7.41(m, 7H), 9.82(bs, 2H),                                    [CDCl.sub.3 ].                                                    mp. 122˜130° C.                                19 Cbz (1 cis: 5 trans)                                                                 H                                                                                  ##STR92##                                                                        3420, 2500(br), 1732, 1549, 1302, 1087 (CHCl.sub.3).                          mp. 127˜131° C.                                                              1.16(d, J=7Hz, 1/2H), 1.29(d, J=7Hz, 5/2H),                                   3.46 (d, J=8Hz, 5/3H), 3.68(d, J=8Hz,                                         1/3H), 5.05˜ 5.49(m, 3H), 5.16(s,                                       2H), 5.66˜6.02(m, 1H),                                                  7.08 ˜7.57(m, 7H) [CDCl.sub.3CD.sub.3                                   OD].                                            20 Cbz (9 cis: 11trans)                                                                 H                                                                                  ##STR93##                                                                        3420, 1736, 1548, 1307, 1085 (CHCl.sub.3) mp.                                 120˜123° C.                                                                  1.73(s, 3H), 3.52(d, J=8.5Hz, 11/10H), 3.73                                   d, J=8.5Hz, 9/10H), 4.54(s, 2H), 4.95(brs,                                    2H), 5.26(s, 2H), 6.99˜7.46(m, 7H)                                      [CDCl.sub.3CD.sub.3 OD].                        21 Cbz (1 cis: 4 trans)                                                                 H                                                                                  ##STR94##                                                                        3415, 1732, 1548, 1304, 1076 (CHCl.sub.3) mp.                                 139˜142° C. (decomp.).                                                       1.67(d, J=6Hz, 3H), 3.44(d, J=8Hz, 8/5H),                                     3.64 (d, J=8Hz, 2/5H), 4.49(d, J=6Hz, 2H),                                    5.23(s, 2H), 5.35˜6.05(m, 2H),                                          7.05˜7.41(m, 7H) [CDCl.sub.3CDCl.sub.3                                   ].                                             22 Cbz (1 cis: 2 trans)                                                                 H                                                                                  ##STR95##                                                                        3175, 2520(br), 1732, 1659, 1071. mp.                                         167˜168° C. (decomp.).                                                       1.98(s, 3H), 2.03(s, 3H), 3.82(d, J=8Hz,                                      4/3H), 3.86(d, J=8Hz, 2/3H), 4.87(d, J=7Hz,                                   2H), 5.64 (s, 2H), 5.52˜5.71(m, 1H),                                    7.21(t, J=8Hz, 1/3H), 7.65˜7.69(m,                                      5-2/3H) [CD.sub.3 SOCD.sub.3CD.sub.3 OD].       23 Cbz (1 cis: 2 trans)                                                                 H                                                                                  ##STR96##                                                                        3150˜2200, 1725, 1675, 1620, 1585. mp.                                  170˜171°  C.                                                                 1.67(s, 3H), 1.72(s, 3H), 3.22(d, J=7Hz,                                      2H), 4.54(brd, J=8Hz, 2H), 5.23(s, 2H),                                       5.30(brt, J= 8Hz, 1H), 6.38(s, 1H), 6.99(s,                                   1H), 7.40(m, J= 7Hz, 6H) [CD.sub.3 SOCD.sub.                                  3 ].                                            24 Cbz    H                                                                                  ##STR97##                                                                        nd          TLC[EtOAc/CHCl.sub.3 (1:1)]: Rf=0.2             25 H      Me  Me  3200, 1720, 1625,                                                                         3.44(d, J=7Hz, 2H), 3.75(s, 3H), 3.85,                                        3.88(2×s,                                    (HClsalt       1605. [CHCl.sub.3 ].                                                                      3H), 6.70, 6.75(2×s, 1H), 6.97,                                         7.43(2×t, J=7                                                           Hz, 1H) [CDCl.sub.3CD.sub.3 OD].                26 BOC    Me  Me  3415, 1720, 1541,                                                                         1.52(s, 9H), 3.54(d, J=6.5Hz, 2H), 3.64(s,                                    3H),                                               (trans)        1155 [CHCl.sub.3 ].                                                                       3.76(s, 3H), 7.11(s, 1H), 7.18(t, J=6.5Hz,                                    1H),                                                                          9.12(brs, 1H) [CDCl.sub.3 ].                    27 BOC    Me  Me  3410, 1720, 1541,                                                                         1.51(s, 9H), 3.54(d, J=6.5Hz, 2H), 3.69(s,                                    3H),                                               (cis)          1150 [CHCl.sub.3 ].                                                                       3.83(s, 3H), 7.03(s, 1H), 7.08(t, J=6.5Hz,                                    1H),                                                                          9.12(brs, 1H) [CDCl.sub.3 ].                    28 Cbz    Me  Me  3390, 1720, 1540                                                                          3.41, 3.48(2×d, J=8Hz, 2H), 3.65,                                       3.73, 3.69,                                                       [CHCl.sub.3 ].                                                                            3.83(4×s, 6H), 5.24(s, 2H),                                             7.00˜7.37(m, 7H)                                                        [CDCl.sub.3 ].                                  29 Cbz    Et  Et  3395, 1720  1.19, 1.20, 1.22, 1.30(4×t, J=8Hz,                                      6H), 3.34,                                                        [CHCl.sub.3 ].                                                                            3.42(2×d, J=8Hz, 2H), 4.08, 4.12,                                       4.15, 4.24                                                                    (4×q, J=8Hz, 4H), 5.21, 5.22,                                           5.24(3×s, 2H),                                                          7.03, 7.13(2×t, J=8Hz, 1H), 7.03(s,                                     1H), 7.31(s,                                                                  5H), 10.15(brs, 1H)[CDCl.sub.3 ].               30 Cbz    Bzl Bzl 3400, 1725  3.31, 3.42(2×d, J=7Hz, 2H), 5.01,                                       5.03, 5.11,                                                       [CHCl.sub.3 ].                                                                            5.17(4×s, 6H), 6.96˜7.30(m,                                       17H), 10.19(brs, 1H)                                                          [CDCl.sub.3 ].                                  31 Cbz    PMB Bzl nd          3.40(d, J=7Hz, 2H), 3.75(s, 3H), 5.10(s,                                      2H),                                                                          5.15(s, 2H), 5.20(s, 2H), 6.8˜7.4(m,                                    16H)                                                                          [CDCl.sub.3 ].                                  32 Cbz    BH  Bzl 3490, 1725  3.34, 3.40(2×d, J=7Hz, 2H), 5.02,                                       5.05, 5.09,                                                       [CDCl.sub.3 ].                                                                            5.17(4×s, 4H), 6.8˜7.4(m, 23H),                                   9.90(brs, 1H)                                                                 [CDCl.sub.3 ].                                  33 HCO    Me  Me  3380, 3140, 1722,                                                                         3.46(d, J=7.5Hz, 2H), 3.66(s, 3H), 3.78(s,                                    3H),                                               (trans)        1705, 1695  7.05(s, 1H), 7.24(t, J=7.5Hz, 1H), 8.49(s,                                    1H)                                                               [CHCl.sub.3 ] mp. 100° C.                                                          [CDCl.sub.3 ].                                  34 HCO    Me  Me  3390, 3150, 1715,                                                                         3.56(d, J=7.0Hz, 2H), 3.73(s, 3H), 3.84(s,                                    3H),                                               (cis)          1700, 1535  7.02(t, J=7Hz, 1H), 7.12(s, 1H), 8.55(s,                                      1H)                                                               [CHCl.sub.3 ].                                                                            [CDCl.sub.3 ].                                  35 HCO    Me  t-Bu                                                                              3380, 1710, 1540                                                                          1.47(s, 9H), 3.50(d, J=7Hz, 2H), 3.86(s,                                      3H),                                               (cis)          [CHCl.sub.3 ].                                                                            7.07(t, J=7Hz, 1H), 7.13(s, 1H), 8.60(s,                                      1H)                                                               mp. 101˜104° C.                                                              [CDCl.sub.3 ].                                  36 HCO    Me  t-Bu                                                                              nd          1.44(s, 9H), 3.27(d, J=7Hz, 2H), 3.80(s,                                      3H),                                               (trans)                    7.05(s, 1H), 7.31(t, J=7Hz, 1H), 8.52(s,                                      1H)                                                                           [CDCl.sub.3 ].                                  37 ClCH.sub.2 CO                                                                        Me  Me  nd          3.50(d, J=6.5Hz, 2H), 3.68(s, 3H), 3.79(s,                                    3H),                                               (trans)                    4.25(s, 2H), 7.24(s, 1H), 7.24(t, J=6.5Hz,                                    1H)                                                                           [CDCl.sub.3 ].                                  38 ClCH.sub.2 CO                                                                        Me  Me  3470, 1725, 1715,                                                                         3.60(d, J=7Hz, 2H), 3.75(s, 3H), 3.87(s,                                      3H),                                               (cis)          1680, 1585  4.27(s, 2H), 7.18(s, 1H), 7.18(t, J=7Hz,                                      1H)                                                               [CHCl.sub.3 ].                                                                            [CDCl.sub.3 ].                                  39 Ph.sub.3 C                                                                           Me  Me  3380, 1720, 1703,                                                                         3.43(d, J=6.5Hz, 2H), 3.26, 3.64(2×s,                                   3H), 3.70,                                         (3 cis:        1500, 1480, 1425                                                                          3.75(2×s, 3H), 6.44, 6.63(2×s,                                    1H), 6.54, 6.70                                    2 trans)       [CHCl.sub.3 ].                                                                            (2×s, 1H), 7.01(t, J=6.5Hz, 1H),                                        7.25(s, 15H)                                                                  [CDCl.sub.3 ].                                  __________________________________________________________________________

What we claim is:
 1. A compound of the formula ##STR98## wherein R isaminothiazolyl or aminothiadiazolyl where the amino group of each isprotected or unprotected,R¹ is hydrogen or halogen, R² is loweralkylene, R³ is (a) hydrogen, (b) a member selected from the groupconsisting of lithium, sodium, potassium, magnesium, calcium andmagnesium, (c) alkenyl having 2-7 carbon atoms or (d) aralkyl having 7to 15 carbon atoms, and R⁶ is (a) hydrogen, (b) a member selected fromthe group consisting of lithium, sodium, potassium, magnesium, calciumand magnesium, (c) alkyl of 1 to 8 carbon atoms, (d) aralkyl of 7 to 15carbon atoms, (e) aryl of 6 to 12 carbon atoms, (f) silyl of 3 to 12carbon atoms or (g) alkenyl of 2 to 7 carbon atoms.
 2. A compoundclaimed in claim 1 wherein R is aminothiazolyl, optionally protected bybenzyloxycarbonyl, t-butoxycarbonyl, methylbenzyloxycarbonyl formyl,chloroacetyl, or benzal.
 3. A compound as claimed in claim 1 wherein R¹is hydrogen.
 4. A compound as claimed in claim 1 wherein R² is straightor blanched chain alkylene of 1 to 3 carbon atoms.
 5. A compound asclaimed in claim 4 wherein R² is methylene.
 6. A compound as claimed inclaim 1 wherein R³ is hydrogen, benzyl, methylbenzyl, p-methoxybenzyl orp-nitrobenzyl.
 7. a compound as claimed in claim 1 wherein R⁶ ishydrogen, diphenylmethyl or p-methoxybenzyl.
 8. A compound according toclaim 1, said compound being2-(2-benzyloxycarbonylamino-thiazol-4-yl)-4-benzyloxycarbonyl-2-butenoicacid.